The cell has a fundamental problem. On one hand it must keep its myriad biochemical reactions apart from its essential and hostile environment, and on the other it must import those supplies that are essential for its survival. Through an elaborate system of supply organs the body provides its cells with appropriate levels of oxygen, salts, water in addition to the fats, amino acids and sugars that provide the cell with its metabolic building blocks. Life is a game of acquisition, and according to the rules the cell must concentrate its resources in much the same way as we accumulate resources from an often inhospitable world. Our bony skeleton provides our internal organs with a framework of support that holds them in protected animation, whilst our elastic and water-proof skin functions as a defining outer membrane for our body, and serves as a reflection of our vitality. Prosperity and survival depend upon efficient trade, whether we consider the prosperity of a cell, an organism or a nation. Our bodies must regularly bring in food, minerals and water through the skin so that we can synthesise and repair tissues, and similarly wastes and excess must be actively lost from the body. Similarly a national economy must export its surplus produce and import its deficiencies for it to grow and flourish. The cell is no exception to the rule of trade, although its transport problems make trade and communication singularly specialised and intriguing.

Life can be regarded as a constant battle against entropy, that fundamental force which drives natural systems towards disorder. Both we and our cells ceaselessly expend energy in order to maintain the concentrated biochemical reactions within that have come to represent life, an order which is restlessly opposed by entropy, demanding that living systems have to work constantly just to maintain their form. Life is this respect is like a sieve into which water must continuously be poured to form a reservoir, the water symbolising vital energy and its never-ending requirement to maintain life. When we rest this vital energy that opposes entropy is revealed in our basal metabolic rate, the six hundred or so calories a day that we need just to stay in one piece. This vital energy is ultimately derived from the sugars, proteins and fats that plants harvest from the sun, molecules that provide the fuel that opposes entropy and drives cellular metabolism ,and which provide the building blocks which are organised to form the unit of life - the cell. Indeed the energy that is required to build and maintain new tissues by the rearrangements of chemical bonds within the food that we eat is appreciable; most certainly from the pregnant mother's point of view. A pregnant mother requires at least eighty thousand extra calories to synthesise her baby, or some three hundred additional calories a day. These eighty thousand calories provide enough energy to power a forty Watt light bulb for two hours and twenty minutes. Towards this great endeavour of creation the mother's womb, comprising the uterus and placenta, provides an ideal environment in which to support the reactions that form new life. Like the cell membrane, the placenta presents a vital and complex barrier which allows oxygen, nutrients and directional signals from hormones to cross into the embryo's circulation, whilst keeping out noxious influences such as bacteria, waste products and toxins that threaten its health and development. The cell faces similar transport problems, although unlike the body which employs specialised organs such as the lung and intestine, and the placenta which has two specialised cell layers that regulate trade between the mother and embryo, the cell, the unit of life, has had to solve these problems of transport using only the essential building blocks of life - its fats, proteins and sugars.

For us to understand how hormones direct the cell and its trade with the cellular nation, we must first understand the essential properties of the cell membrane. The eukaryotic cell (scientific parlance for a non-bacterial cell) is in essence a bag of biochemical reactions, defined and concentrated by an outer limiting membrane that is made up from fatty acids, glycerol and cholesterol. Long fatty acid 'tails' are chemically linked to a special hydrogen-carbon backbone called glycerol. As anyone who admits to frying food will know, fats (referred to as lipids by the monastic order of biochemists) don't care much for water, a property we call hydrophobicity. In contrast, the glycerol 'heads' of membrane lipids, usually found linked to sugars, phosphates or choline as well as to two fatty acid tails, are relatively water-preferring, or hydrophilic. Fill a freshly used frying pan with water and a smooth, thin, yet flawless layer of oil forms at the interface between the air and the water. Scientists imagine the cell membrane as two parallel layers of lipid, glycerol heads facing outward and tails inward, forming a stable and fluid 'bilayer' at the interface between the cell and the dark world that surrounds it. This bilayer results because the long fatty acid tails of membrane lipids avoid water and consequently seek refuge in one another's company, whilst their water-preferring heads face the salty solution present on either side in defiance, creating two surfaces which interact with the cell's watery environment and a hydrophobic core that presents an enormous energy barrier to the crossing of water, minerals and macromolecules. This apparently flimsy membrane, barely a hundredth of a micrometre across, forms the castle walls of the cell, presenting an impenetrable impasse to the passage of most ions and molecules except at jealously guarded portals that are formed by proteins embedded within the membrane walls. The cell membrane and its proteinaceous portals collude to collect nutrients and repel the unwanted, ferrying goods and information into the cell to sustain the castle's economy.

As the cell reveals, trade is in essence a fundamental pattern of Nature, and not an invention of the human species. Flowers provide nectar and in exchange insects transfer pollen - it's a fair deal. Likewise the body provides the cell with warmth, oxygen and nutrients (and of course garbage disposal), and the many specialised cells of the body in turn provide the body with its various essential services, including the absorption of oxygen and nutrients across the lung and intestines, hormone secretion from glands, and movement through muscle contraction. The body can be regarded as being rather like the economy of a city, with many specialised individuals contributing towards the economic whole, where the whole is much greater than the sum of its diverse components. Nutrients, salts and water are readily brought in, and wastes lost by the opening of the various pores in our skin. Though apparently complete and blemish free, the oily layer in the frying pan is however delicate, easily disrupted by a finger or spatula. If such a momentary loss of integrity of the cell membrane were to occur, the delicate balance of salts, nutrients and metabolic reactions contained within the cell would be lost instantly and the cell would die. Clearly, other means had to be evolved for the cell to bring the good things in and keep out the bad, allowing cells to grow, multiply and function towards the good of the whole. In this respect the cell membrane is perhaps the defining specialisation of the eukaryotic cell, its properties dictating communication and trade across the cell membrane.

With the notable exceptions of the exhaust pollutant nitric oxide and the family of 'steroid hormones' which include oestrogen and corticosterone, signals carried by hormones and transmitters do not generally dissolve in fats and hence cannot cross the cell membrane. Clearly other mechanisms had to evolve to allow the hormonal message to be received by the internal workings of the cell. Without the direction of hormones and other chemical messengers the many billions of cells within our bodies would simply lose direction and squander resources aimlessly. Metabolism would fail to slow down in hot weather as we would overheat; fats would not be liberated for essential fuel during lean times, and levels of glucose in the blood, maintained diligently at between one and two grams per litre, would stray too far. Too much, or indeed too little blood glucose, and the neurons of the brain cannot function properly and die, and thus life itself balances upon a knife edge of fine hormonal control.

To achieve this vast undertaking of integrating the body's many essential services, evolution commissioned specialised cells to release hormones that encode changes in both our internal and external environments, and like a newspaper, hormones have a broad circulation. For hormones to finely control and tune the body's organs to match supply with demand, they must be released and circulated in appropriate concentrations over carefully regulated periods of time. For example, a sudden exposure to an external threat or stress, such as a charging bull or an irate boss, and there is an immediate need for energy to accompany the newly found motivation. Adrenaline, the emergency 'fight or flight' hormone, is released from the chromaffin cells of the adrenal medulla after a delay of only a few thousandths of a second due to rapid stimulation from incoming sympathetic nerves. The adrenal medulla is an example of an endocrine gland, releasing its hormones into the bloodstream in response to a stimulus, in this case the perception of threat or danger. Within its sphere of influence adrenaline causes an increase in both the rate and output of the heart, changes that are accompanied by a reduction in the resistance of the blood vessels to ensure that the supply of oxygen and nutrients to the muscles, brain and periphery matches demand. Adrenaline is perhaps the body's simplest hormonal signalling system, where the levels of a single hormone increase and subside with the perception of threat, its sphere of cellular influence defined by the limits of the circulation and the number of cells that have an ear to listen.

In contrast, the hormonal system that controls the level of blood sugar has to ensure that glucose levels do not stray too high or too low, and thus forms an oscillating control system much like a thermostat, rather than the graded hormonal switch provided by adrenaline. If blood sugar levels exceed socially acceptable limits, then non-diabetics respond by releasing the hormone insulin from cells that have specialised to become efficient glucose sensors. These cells, referred to as beta-cells, are found within the pancreas, another of the body's endocrine glands. If an individual has consumed more calories than are immediately needed, then the rush of glucose into the bloodstream from the liver and intestines triggers the release of insulin from the beta cells, insulin acting as a countermeasure to lower blood glucose by instructing the cells of the liver, muscle and adipose tissues to increase its uptake from the circulation. In the liver and skeletal muscles this surplus glucose is stored as glycogen or converted into amino acids for protein synthesis, and in the fat cells of adipose tissue the glucose is used to synthesise lipid. Conversely, if blood glucose levels fall below the safety threshold of four millimoles per litre during a prolonged fast, the antagonistic pancreatic cousins of the beta cells, the alpha cells, release the hormone glucagon to remedy the situation. In response to glucagon the same tissues then respond by breaking their storage macromolecules down into their components to provide fuel. Muscle proteins are broken down into their constituent amino acids; muscle and liver glycogen is broken down into glucose and lipids stored within adipose tissue are broken down into their component fatty acids and glycerol. The liberated amino acids accompany the glucose back into the circulation and travel to the liver where they are metabolised into glucose and ketone bodies, the only two forms of fuel that the brain can utilise. Whereas most cells in the body can use fats and proteins as a source of energy to drive metabolism during lean times, when glycogen reserves have been depleted and blood glucose levels remain low the brain relies heavily upon ketone bodies to make up the shortfall. Ketone bodies may sound unfamiliar, but are better known to us as those odorous residues that linger in the early morning air around the city's sidewalks, marking the nocturnal passage of the malnourished. Together the liver, skeletal muscles and adipose cells are the grain houses of the body, storing food for the cellular community during times of plenty for subsequent release in times of need:- insulin and glucagon the warring messengers that contradict one another in order to signal the balance between supply and demand.

In any large company or society of individuals the highest levels of productivity and growth are achieved through co-operation. Growth however, must ultimately be limited by the availability of resources, and even competition between individuals, necessary for the efficient exploitation of resources, can only enhance growth within a society so far, whether that society consists of billions of cells, hundreds of individuals or a society of nations. Resources permitting, growth can be maintained by closely matching supply with demand, and maximised if each cell, like the many individuals within an industrialised society, specialises to provide a service or product with concentrated efficiency. The more the labour is subdivided, the more efficient each service becomes, until a single-celled organism has evolved into a complex multicellular animal with many tissues or a street trader has grown to become a multinational distribution company. When many such specialised individuals act in concert to accomplish a given task, whether it be white blood cells fighting an infection, lionesses hunting for prey or Intel producing a new integrated processing chip, the efficient performance of the tasks allocated by each member of the company is necessary to ensure subsequent growth and expansion within a competitive world. Specialisation facilitates complexity, complexity makes for the efficient exploitation of resources, creating still further opportunity for growth. Yet such ever increasing specialisation has a major drawback. Sub-specialisation necessitates ever more elaborate mechanisms of communication to ensure that precious effort and resources are not wasted. This central theme of communication is one that holds all societies together, whether they be multi-cellular organisms or global markets. If most cells and individuals are highly specialised in their product, no system, whether it be human or biological, can hold together and expand efficiently unless its activity is co-ordinated by the efficient measurement, integration and distribution of information. Evolution has therefore, through countless millions of generations of trial and error, developed a variety of elaborate signalling systems to maximise the efficiency of the cellular nation. Information is transferred at great speed and over long distances by networks of nerves governed by a central processor that we call the brain. Local communication within specific tissues is mediated by circulars of hormones, whilst more global trends in the body are carried by endocrine hormones through the circulation to those cells with an ear to listen. The cell's metaphorical ears are provided by a mosaic of protein receptors embedded within its membrane that listen, integrate and carry information across the membrane.

Signals from the outside world provide us with essential information that guide us to the presence of those resources and threats which determine our survival. This essential information must be collected by our sensors, those specialised arrays of receptor cells that lie at the interface between our internal selves and our external world. Yet the sensors that are formed by the eyes, ears, skin, tongue and nose are selective in the information that they sample from the ocean of signals that are potentially available to them. Information concerning ambient temperature, light intensity, surface texture, the frequency of sound and the chemical composition of our environment (perceived as smell and taste) is continuously sampled and converted from a chemical or physical stimulus into an electrical signal. Such signals are then encoded into nerve impulses which can be read, integrated and interpreted by the brain before being dispatched in the form of chemical and electrical signals to the relevant departments of our organ system for appropriate action. Cells can similarly sense changes in their external environment through an array of sensor proteins upon their surface that are referred to as membrane receptors, proteins that detect, transmit and alter the information that is carried by a hormone into a form which the cell can interpret..

How do the various cells of the body and sensory organs capture signals and transfer the vital information across the membrane without disrupting their precious environment? The answer lies in proteins, or rather in the remarkable range of properties that Nature's repertoire of some twenty different amino acids confers upon them. Proteins are assembled from amino acids linked end to end to form a backbone, each amino acid contributing a side chain that projects away from the centre, contributing a distinctive size, hydrophobicity, electrical charge and chemical reactivity that together determine the properties of the protein. If an amino acid can be imagined as a letter, then a protein is a sentence, and every cell a book. In the case of receptors, or rather the many hundreds of different proteins that serve to capture and discriminate between hormonal signals, the sequence of amino acids that form the backbone of the protein are uniquely tailored to capture and carry vital information across the cell membrane. In order to perform their task, that part of the receptor that is exposed to the outside world must contain amino acid residues that prefer the company of water, residues that form a three dimensional 'conformation' that recognises the hormone of interest. Secondly, the central regions of the protein backbone must contain stretches of twenty or more hydrophobic amino acids that generally prefer the interior of the membrane to that of the charged salt solutions that bathe either side of the membrane. Such hydrophobic sequences readily become inserted into the membrane bilayer, defining the receptor protein's shape and location within the membrane. Perhaps most importantly, the membrane spanning regions of the receptor are responsible for carrying the hormonal signal across into the cell to the internal regions of the receptor, where the receptor signal is ultimately translated into a form that the components of the cell can understand. A receptor protein, much like a set of traffic lights, signals three states of activity within the cell; systems go (green); ready for change (orange) and stop (indicated by the universal red). Proteins behave much like traffic signals in the sense that they have a number of shapes, or conformations that are dictated by their various interactions with hormones, and when a hormone binds to its receptor the metaphorical light turns green, and the receptor conducts a signal that enables it to transform the activity of the cell.

However for efficient communication to take place an exchange of information must occur; the receptor must pass its information onto the cell and the cell in turn must reply to the receptor to confirm that the message has been received and understood. Just as the cell listens to the receptor, the receptor in turn listens to the cell, and the receptor's ears are found within its intracellular regions which frequently contain stretches, or sequences that are rich in the amino acids threonine, serine or tyrosine. These three amino acids share in common side chains that have the chemical properties of water, allowing them to receive information from the cell in the form of dense negative charges carried by phosphate molecules. Such phosphate groups are readily added onto or removed from these three amino acids by specialised enzymes known as 'kinases' and 'phosphatases' respectively, and the dense negative charge that they carry modifies the shape and the signal carried into the cell by the receptor protein, thus changing the proportion of time that it spends in its red, orange or green states. Thus the phosphate modification, or phosphorylation of receptor proteins provides a feedback pathway to ensure that receptor sensitivity and information transfer is precisely tuned to mirror the activity of the cell and its capacity to respond to further stimulation. Such a persistent activation of receptors may cause them to desensitise, or become less effective at transferring signals across the membrane, rather as the ear becomes accustomed to background noise or the eye to background light. Alternatively the addition of phosphates may enhance signal transfer, for the down-regulation of one receptor by phosphorylation such as insulin may conveniently coincide with the up-regulation of the glucagon receptor to tip the balance of the see-saw with the general swing of events. There are in addition other mechanisms by which the receptor listens to the cell, but these are often secondary or additional to the key strategy of receptor phosphorylation and serve the same end:- to match the throughput of information to the cell's capacity to respond, and as importantly to ensure that a hormonal signal has an end as well as a beginning.

Receptors are classically imagined as a lock that can only be opened by a very specific key, namely a hormone or transmitter of a defined shape, or at the very least a very good skeleton key. However, to the discriminating mind this analogy does not survive scrutiny, because biological molecules such as hormones and transmitters differ from keys, and receptors from locks, in that their various regions not only possess specific shape, but also a defining distribution of electrical charge, affinity for water and for each other. Thus as a biological lock the receptor responds not only to the shape of the hormone, but also to its distribution of charge and hydrophobicity, making biological receptors more akin to Cinderella's shoe than a multi-lever Union lock. Hormones don't just fit their receptors, they interact with them, just as the curvature of Cinderella's shoe was precisely moulded to fit the delicate, unique and shapely contours of her foot allowing her prince to find his true partner.

Receptors serve as a molecular bridge by which water-borne signals cross the membrane, but before they can be understood by the cell, they must first be translated into a language that the cell understands: a change in the chemical balance of the cell. These signals are known as second messengers, and are generated following the activation of a receptor by the primary messenger, such as a hormone or transmitter, and may be generated by a startling variety of mechanisms. Some second messengers are metabolic derivatives of the cell's basic building blocks, synthesised by off-shoots of well-worn biochemical pathways, or they may take the form of specialised proteins that transfer phosphate groups to and from specific cell proteins and lipids, whilst some second messenger signals are provided by changes in the levels of charged ions or radicals in the cell, such as calcium, nitric oxide, or even the pH of the cell. Second messengers carry receptor signals into the cell's metabolic heartlands where they are integrated to direct changes in the activity of the cell's various engines that include its metabolic machinery, protein skeleton and centre of intelligence - its nucleus. Through carefully regulated changes in the levels of specific second messengers changes in the cell's environment can be transduced into signals that can be interpreted and acted upon by those cellular proteins that decipher and copy the genes. Genes are thus environmental sensors, responding to their external world by producing more or less of whatever protein is necessary, allowing the cell to adapt to the pressures of change and contribute to the survival of the cellular nation.

All functions and reactions within the cell are carried out, or are at least regulated by proteins. Proteins must therefore be almost limitlessly versatile in their capacity to perform molecular tasks, and are indeed theoretically capable of performing almost as many different functions as there are proteins that can be made. For a protein only a thousand amino acids in length, the number of possible arrangements of the basic repertoire of amino acids is twenty to the power of one thousand, a value greater than the number of atoms in the universe. This incredible versatility allows proteins not only to function as receptors and transducers of signals, but to make and break chemical bonds in apparently endless metabolic pathways, providing the cell with a defining skeleton, allowing it to read and copy the genes, and indeed perform countless other tasks associated with the control of shape, movement and the storage and integration of information. The cell's complement of proteins behave like an orchestra in concert to the tune of its receptors, responding to the many subtle flickers of the conductor's hormonal baton that sweetly and smoothly change the cell's tune to match the mood of that great concert hall that is the body. Through their receptors hormones finely control the diverse functions of the body's cells, including the secretion of fluids, muscle contraction, the division and subsequent specialisation of cells (a process known as differentiation), and the generation of explosive waves that mediate the chatter between nerve cells. Hormones and their receptors may not be able to change a cell's inheritance, but they most certainly direct it.

For any given cell, as for any given animal, an inappropriate response to an event or stimulus within its immediate environment can spell disaster. An animal that fails to fight or take flight from a predator, to pay appropriate homage to a higher social animal or to take advantage of foraging opportunities will almost certainly fail within a competitive environment. In much the same way, a cell will fail and die if it does not respond quickly and appropriately to an infection, to positional cues within in a bustling and congested cellular society, or to fluctuations in the supply of nutrients and hormones that portend greater changes in the whole. Clearly receptor signals had to evolve to be sufficiently fast to enable us to respond rapidly to changes in our environment. For instance, those receptors which are present upon nerve cells and at the junction between nerve and skeletal muscle cells transfer the signal from an incoming nerve cell, or neuron within a few thousandths of a second. Such signals are, however, as short-lived as they rapid, requiring a highly specialised receptor design that is in sharp contrast to that of a second class of receptor which communicates trends rather than instantaneous decisions to the cell. This second class is typified by receptors that convey the responses of cardiac muscle cells to noradrenaline released from the sympathetic nerves which supply the heart, and by those receptors which are found upon the surface of olfactory receptor neurons and confer our sense of smell. Noradrenaline augments the rate and output of the heart by enhancing the entry of calcium ions into the muscle cells that power the ventricles of the heart. In isolation cardiac muscle cells take many seconds to respond to noradrenaline, requiring more than ten minutes to reach the peak of their response to the hormone. Responses to this class of receptor are generally long lasting, and require many minutes to return to their original levels after the removal of noradrenaline. There is however also a third class of receptor, employed by those hormones that we collectively refer to as growth factors. Receptor responses to growth factors are usually slow in onset and prolonged in action, mirroring those changes in cell function that they regulate. Growth factor receptors govern the survival, growth, division and specialisation of cells, and part of their action involves activating programmes that lie latent within the genes, thereby altering the release of information into the cell.

For us to understand the mechanisms by which information is transferred across the membrane and into the cell, one more of its essential properties must be appreciated. The development and acquisition of a fatty cell membrane was essential not only for the generation of biosynthetic compartments optimised to support growth and metabolism within the cell, but as importantly the cell membrane functions as a capacitor that can store electrical charge, and with the right conductive elements inserted, as a battery. A capacitor is essentially a layer of insulating material that separates two conducting regions, which is, in effect, exactly what the cell membrane is. Moreover, the thinner the insulating layer, the greater the charge that can be stored across it, making the cell membrane ideally suited to the task of storing electrical charge, or potential. The Californian drive towards clean transport technology has spurred a race for new battery technologies. Nature however has beaten man to the task by many hundreds of millions of years by designing a battery that is capable of storing a very considerable electrical charge without the great impediment of weight. The lead-acid batteries of an electric car may weigh some five hundred pounds, yet give the electric car a range of only some fifty miles in-between lengthy recharging. Species of electric fish such as the California ray (Torpedo californica) or the electric eel (Electrophorus electricus) possess an electric organ that is capable of repetitively discharging some seven hundred and fifty Volts for the price of a mere few pounds in weight. It may well be the case that we can adapt such natural technology towards the practical application of such "self-renewing" biological batteries that are composed of assemblies of living cells rather than the bulky and inefficient nickel-cadmium and lead-acid batteries that serve us now. Electric organs are made up from many thousands of electroplax cells all connected in series to combine their output, like many one-and-a-half Volt batteries lined up in sequence to power a toy or music centre. Consequently the large voltages produced by the electroplax organ of these fish arises from the synchronous discharge of many thousands of such tiny electroplax cells, each contributing a small, but synchronous discharge of voltage.

A further understanding of the molecular world of the membrane is required before we can appreciate how charge is stored across the membrane capacitor, and just as importantly, how this stored charge is dissipated. Perhaps the first surprise of this enquiry is that we can begin to grasp the importance of maintaining the mineral balance within our body fluids. The salty solutions that bathe either side of the cell membrane are rich in oxygen, nutrients and mineral salts, but the mineral composition of these two solutions are very different. Potassium, sodium, calcium and magnesium are metallic ions that are essential for life, present in vast quantities within the mineral salts that make up the soils, bedrocks and seas of our planet, and these mineral ions are required in substantial quantities by the body, whereas other metallic ions such as zinc and manganese are needed in trace quantities only to maintain vitality. Ions are charged atoms, that have either gained or been stripped of electrons, conferring upon them a defining charge. Atoms seek stability through chemistry, and metals are as-called because they tend to become chemically more stable when they lose an electron or two, whereas their non-lustrous counterparts, the unimaginatively named family of non-metals which includes sulphur, oxygen, phosphorous and chlorine must gain electrons to fill in the holes in their outer orbit in order to maximise their stability. The greater this inherent drive to gain or lose an electron, the more reactive the atomic form of an element is said to be, creating a spectrum of reactivity spanning from the relatively inert gold or semi-metal silicon to the explosively reactive fluorine gas and caesium metal. Metal and non-metal ions react together readily to find a mutual solution to their appetite for stability, and once metal atoms have reacted to form positively charged ions they readily form salts with their negatively charged non-metal counterparts which are often very soluble in water. Salts of metals and non-metals, such as sodium chloride or potassium phosphate, dissolve in water to release the individual ions that were previously held together by electrostatic interactions, and it is the role of the cell membrane to partition these various ions together with their associated charge, and this segregation forms the basis for the electrical excitability that enabled complex multicellular organisms to evolve.

The fluid bathing the surface of the cell is rich in calcium and sodium chloride, in sharp contrast to the fluid with the cell which is enriched in potassium chloride. The great variation in the supply and requirement of these diverse ions by the body's various compartments created an additional evolutionary transport problem for cells, the need to selectively control the movement of ions across the cell membrane. Receptors are, therefore, not the only class of proteins that span the cell membrane and regulate the transport of materials across it. All cells contain a diversity of specialised transport proteins that selectively ferry ions and nutrients both into and out of the cell which would otherwise be unable to cross the hydrophobic barrier presented by the cell membrane. As a favourite old Physics teacher would constantly preach, in the natural world you simply don't get something for nothing. That 'something' is the capacity to move a water soluble ion across the barrier presented by the cell membrane, and the cost is that energy which is consumed by the membrane pumps as they restlessly battle to move ions across the cell membrane against their prevailing gradients of concentration. In fact, on many cells just two protein ion pumps are ultimately responsible for the large differences in the concentration of metallic ions that are present across most cell membranes, and these are powered by the release of energy trapped within the bonds present between the phosphate molecules of adenosine triphosphate (ATP), the cell's universal currency of energy. One of these two ion pumps is known as the 'calcium ATPase', which expels calcium ions from the cell. The calcium ATPase works tirelessly to create and maintain a gradient where the concentration of free calcium ions outside the cell is as much as ten thousand times greater than the concentration found inside the cell. In contrast, the close relative of the calcium ATPase, the ubiquitous sodium-potassium ATPase ejects unwanted sodium ions in exchange for potassium ions which are thus accumulated within the cell's salty interior, and the faster sodium ions enter an excited cell, the harder the energy-consuming sodium-potassium ATPase has to work to expel them again. Digitalis, the toxin present in the foxglove, specifically poisons the sodium-potassium ATPase, and in doing so collapses the ion gradients that support the body's excitable cells, and in particular the sodium-potassium ATPase of the heart, stopping the very rhythm of life. Between them these two pumps establish the three asymmetrical gradients of ions across the cell membrane that underlie the basis of the electrical excitability of the cell. Calcium and sodium ions are present at much higher concentrations outside the cell than are found inside, and can be imagined as being rather like great lakes dammed above a river valley, an instability that prevails in apparent balance until the sluice gates of the dam are opened and the water rushes down into the valley below as fast as the aperture of the sluice gates will allow. Therefore, if pores within the cell membrane which are permeable to sodium ions are suddenly opened, sodium ions will rush through them into the cell's interior through these biological sluice gates.

We can now introduce a third class of membrane spanning protein into the equation, joining the receptor and pump proteins whose acquaintance we have already made :- the ion channel. An ion channel is a protein that controls the diameter of a pore that perforates the cell membrane. Ion channels exist for the purpose of dissipating electrical gradients, that is to say that they, like the sluice gates of a dam, permit certain ions to move across the cell membrane in the direction dictated by the prevailing electrical and concentration gradients. This to the biophysicist is as straight-forward as saying that water cannot run uphill, and the same holds true for ions, the exception being that the 'pressure' upon an ion to move in a certain direction is determined not only by the electrical gradient across the cell membrane but also by the gradient of its concentration across the membrane. Once an ion channel has been opened then ions will continue to flood across the membrane until either the ion channel's gate has been closed again, or alternatively until the charge carried by the ions passing through the ion channel accumulate upon the other side of the membrane to such an extent that the resulting charge opposes any further flow. In less convoluted terms, the 'pressure' driving the movement of a particular ion across the membrane is determined both by the difference in its concentration, and by the difference in the electrical charge that is present across the membrane capacitor.

However, in contrast to the sluice gate of the dam, ion channels have the additional property of selectivity, in that they often allow only one 'species' of ion to pass through their pore when open. Ion channels are thus inherently racist as border immigration goes, some permitting the movement of only potassium ions across the membrane, others are exclusive in their preference for sodium ions, whilst another class of ion channel allows both calcium and sodium ions to pass through. In contrast other families of ion channel are exclusively selective for negatively charged ions such as chloride or bicarbonate. So why did evolution, that relentlessly efficient engineer, generate such a diversity of ion channel families? Each class of ion channel plays a very different role in controlling the excitability and activity of the cell. Ion channels that allow sodium ions to flood into the cell generally cause excitable behaviour in cells, driving such cellular processes as nerve transmission and muscle contraction, whilst ion channels that selectively allow calcium ions to flood into the cell tend to serve as triggers, causing the release of transmitter from nerve terminals, the secretion of hormones from endocrine cells amongst other excitable cellular processes. In contrast, those ion channels which are selectively permeable to potassium ions, the concentration of which is much higher within the cell, tend to reduce the excitability of cells when open because they allow positive charge to leave, rather than to enter the cell and thus exist to provide a counterbalance to sodium and calcium permeable channels. The role of chloride channels tends to vary considerably between cell types along with the difference in chloride concentration that prevails across the membrane. Chloride channels play an important role in regulating the digestion of food, reducing the electrical excitability of nerve and muscle and driving the secretion of fluid by glands. Different types of ion channel thus evolved to rapidly guide and alter the behaviour of various types of cell and without them, as we shall see, the rapid transmission of information within complex living organisms could not have been.

Cambridge's Alan Hodgkin and Andrew Huxley were the first to demonstrate that discrete fluxes of potassium and sodium ions, separated in both direction and time, were responsible for generating the waves of potential, known as action potentials, that travel along nerve fibres. It wasn't until some three decades later that the individual sodium channels responsible for the generation of these waves were first visualised by Germany's Bert Sakmann and Erwin Neher using the new technology of membrane "patch-clamping", a method that allows currents as small as a tenth of a millionth of a millionth of an Ampere to be detected. An interest in ion channels was not the only notable feature these two groups shared in common, for they both later won the Nobel prize for the immense impact their discoveries had upon medicine. Hodgkin and Huxley worked with the squid giant nerve fibre, or axon, a high speed information thoroughfare for action potentials that travel the length of the squid's body. Action potentials have been clocked travelling at speeds of up to fifty miles an hour in the squid giant. Such speeds are a measure of the rate at which the 'depolarising' electrical wavefront, caused by the entry of sodium ions, moves along the nerve fibre. The front of the wave triggers the explosive opening of voltage-sensitive sodium channels immediately ahead to perpetuate the wave's progress, much as an ocean wave ploughs into the calm waters ahead of it to continue its relentless advance. Meanwhile, in the wave's wake potassium channels open, and potassium ions flood out of the cell to restore the electrical charge across the membrane to its state, just as a hollow follows the ridge of an ocean wave.

The explosive influx of positive charge carried by the sodium ions in an action potential is in part due to the high concentration of sodium ions that prevails outside the cell, and because the internal face of the membrane is maintained at a potential some fifty to ninety thousandths of a Volt (milliVolts) more negative than the external face of the membrane in the resting nerve axon. But why is the resting membrane potential of an unstimulated nerve fibre relatively so negatively charged, making the electrochemical gradient encouraging the entry of positive charge carried by sodium and calcium ions so much greater than that for potassium to leave the cell? The explanation for this phenomenon is, however, surprisingly straightforward, as 'resting', or unstimulated cells are in the habit of leaking potassium ions, rather as a government department has a tendency to leak white policy papers. In other words, many more potassium channels are found to be open in the unstimulated nerve cell than sodium or calcium channels, which tend only to open after they have been triggered to do so by the binding of a hormone or a change in the voltage across the membrane. Such a steady and unopposed leak of positive charges from the cell carried in the form of potassium ions causes negative charge to accumulate upon the inner face of the cell membrane capacitor, that is until a potential is reached where the build up of external positive charge is sufficient to counterbalance the concentration gradient that drives potassium ions to leave the cell. At this point Nernst's equilibrium is reached, a balance which we measure as the resting membrane potential of the cell.

With this understanding we are now able return to the central theme of receptors and how the electric eel can discharge its powerful batteries at will. The secret lies in polarity, for the electroplax cell has two faces; one that receives a rich innervation of nerve terminals which release acetylcholine, and one that doesn't. At rest the constant leak of potassium ions pushes the membrane potential of both faces of the cell towards minus ninety milliVolts, and no net current flows between the two terminals of the electroplax cell as they both are both at the same potential, and are said to be isopotential. So how does the electrical potential across the cell membrane get turned into an electrical potential across the entire cell that is sufficient to generate an electric shock? The answer lies in the properties of the class of membrane receptors that mediate the rapid transfer of information between the nerve terminals, in this case the acetylcholine receptor. It took many scientists the best part of a decade to unravel the molecular structure of the acetylcholine receptor, allowing us to understand the molecular secrets underlying this remarkable speed of information transfer. Scientists sat enthralled as the dark, shadowy outline of the acetylcholine receptor with its five turrets and pentagonal structure was first revealed by Nigel Unwin. In the electroplax organ nerve terminals contact the surface of the electroplax receptor cell, where they release acetylcholine into a tiny cleft situated between the nerve terminal and the electroplax cell, a cleft that is less than a tenth of a micrometre across. Within tenths of a millisecond the transmitter has made its way from one side of the synaptic cleft to the other where it reaches and binds to receptors that are found exclusively upon this innervated face of the electroplax cell. The binding of two such large, charged and highly polarised acetylcholine molecules to the receptor causes the movement of bonds within the structure of the acetylcholine receptor, much as twisting a retractable ball point pen causes the core to move slightly due to a change in the tension within the spring. The acetylcholine receptor is now in its ready, or orange phase. Then within a imperceptible instant, a few tenths of a millisecond in duration, the orange light has disappeared. Thirty millionths of a second later something suddenly gives. Movements of chemical bonds within the acetylcholine receptor have put sufficient tension with the molecular spring, and there is a rapid rotation leading to a retraction of regions containing bulky amino acids that previously occupied the receptor core. The light has turned green, and the receptor's jealously guarded secret is explosively revealed as positively charged sodium ions flood through the receptor and into the electroplax cell, depolarising the membrane of the innervated surface. The receptor is itself an ion channel, and once open, all that remains as a barrier to prevent all ions from flooding into the electroplax cell are three concentric rings of negative charge that line the pore of the receptor-channel, a property that is contributed by the amino acids glutamate and aspartate. These three rings of negative charge serve to repel all negatively charged chloride ions and positively encourage sodium ions to enter the cell, simply because unlike charges attract and like charges repel.

Hence the arrival of a centrally generated action potential at the electroplax nerve terminal triggers the explosive release of acetylcholine, an event that is closely followed by an equally explosive entry of sodium ions into the electroplax cell. Such a flood of positive charge across the innervated face of the electroplax cell causes the potential at the inner face of the membrane to change from a negative potential of ninety milliVolts to a positive one of sixty milliVolts within milliseconds of the arrival of the action potential, a net change of some one hundred and fifty milliVolts in all. However, because the opposing face of the electroplax cell is not innervated or exposed to acetylcholine, it remains at the cell's resting potential of minus ninety milliVolts, and consequently the one hundred and fifty milliVolt change in potential will occur not only across the membrane face that is adorned with acetylcholine receptors, but also across the entire cell. Yet these one hundred and fifty thousandths of Volt do not correspond to the much vaunted seven hundred and fifty Volt shock that can be delivered by an agitated eel. As anyone who has wrestled with a child's toy car or a large battery-operated radio will recall, many small batteries connected end-to-end are required to generate the power needed to drive such an energy-consuming system. Some five thousand such tiny electroplax cells acting in series, each generating a 150 milliVolt output, are sufficient to produce a discharge of 750 Volts, amounting to more than three times the output of a British power point (or six American power points). So now we appreciate how an eel can generate such a discharge, yet one further question remains. Exactly how does the eel switch off the power? Like a traffic signal, the acetylcholine receptor-channel has a built-in time switch, and within a second of opening the flow of sodium ions stops abruptly as the tension in the molecular spring that was generated upon binding acetylcholine is abruptly released, enabling the bulky amino acids that were displaced to return to their original position and block the channel pore. The cycle is now complete:- the signal is red. Now the array of acetylcholine receptors are in a 'refractory', or insensitive state, unresponsive to further stimulation until the ever busy sodium-potassium ATPase and potassium channels have conspired to remove the transgressing sodium ions and return the membrane potential to its resting value of minus ninety milliVolts in readiness for another discharge, for all natural systems are cyclical.

As the junction between nerves and electroplax cells amply demonstrate, evolution has found a solution to the problem of generating fast signals in the receptor-operated ion channel, a development essential for both hunter and hunted alike in the competitive struggle for existence. Indeed the emergence of so many different subspecies of such 'receptor-operated' ion channels, each responding to one or two members of a spectrum of transmitters, has enabled the rapid processing and integration of many different sources of information within the brain. In fact the enlargement of the forebrain, and the increased information processing power that accompanied it, came to represent the crowning evolutionary advance of the hominids. Perhaps the pressure to survive within an increasingly complex and technological world might eventually encourage our cerebral capacity and forebrains to enlarge still further, at least within one pool of the breeding population. The evolution and refinement of the receptor-operated ion channel has endowed the brain with the capacity to integrate and process complex signals within hundredths of a second, signals that are ultimately derived from the arrays of internal and external sensors that contribute all information relevant to survival. The receptor-operated ion channel is the fast receptor mechanism that permits thought, sensory processing and movement, our three principal tools of survival. But what receptor mechanisms evolved to mediate less abrupt processes, such as changing the output of the heart or detecting odours, signals that may persist for minutes or even hours. Clearly a system that switches off as quickly as it switches on is of no use to a wine taster or for a long game of squash. For the best illustration of the solution to this second role for membrane receptors we can defer to our sense of smell to savour Nature's marvel of molecular engineering.

The detection of odours, or olfaction, is an extremely precise, accurate and memorable process that allows us to reliably distinguish between different odours, from the aromatic smell of almonds to the caprillic odour of ripening cheese, and from the fragrant smell of fresh flowers to the pungent odour of hydrogen sulphide. There are as many as a thousand different odour-detecting receptors within the lining of the nostrils that constitutes the mammalian olfactory organ, with the combined capacity to detect and discriminate between as many as ten thousand different odour-producing molecules, or odorants. In this, and indeed most respects, olfactory receptors are remarkably similar in their properties to those receptors that are present upon the cell membrane. Receptors have the all important and defining property of specificity, in that they exhibit a remarkable level of discrimination in what they bind to, each receptor responding to only a very selective range of molecules, whether they be hormones like insulin or adrenaline, transmitters like acetylcholine, or in the case of the olfactory receptor, odorants. This specificity, or capacity to discriminate between information sources which afford us with detailed information about the chemical makeup of our environment (which we perceive as tastes or odours), limits our perception. The sensitivity and specificity of the tiny patches of olfactory epithelium that lie behind the bridge of the nose enrich our sensory perception to a point where it becomes defining to our very sense of being. Smells enrich our memories as we recall the musty smell of old books in the school library, and the sharp scent of freshly cut grass on a Sunday afternoon before the rich flavour of mother's Sunday lunch wafted through the kitchen window. Indeed if our various cellular receptors did not possess such levels of discrimination, then less useful information could be derived from our environment because of the unwanted 'noise' that would result from the competition between different molecules attempting to bind to the same receptor. This is of crucial importance, as without a high level of receptor specificity, a signal intended for one pathway will trigger others, desensitising them from their main task and blurring the distinction between signals to the point where our sensory world would become demonstrably impoverished. We do not have to imagine such a world, for receptor deficiencies such as colour-blindness are commonplace. However, as primates our sense of smell has been somewhat relegated in its importance in relation to other members of the animal kingdom. Although we can detect odours such as vinegar (acetic acid) if there are as few as five hundred thousand million molecules of the chemical within a cubic metre of air, a dog can detect as few as two hundred thousand molecules within the same volume. Regardless of the remarkable acuity of the human sense of smell, the dog's olfactory system is over two million times as sensitive, putting our sensory prowess firmly into perspective and perhaps raising our level of esteem for our best friend as he is dutifully obliged to fetch that well-worn bedroom slipper.

Inhaling through the nostrils causes air to rush in and over the tufted patches of olfactory epithelium that resemble a pile carpet under the electron microscope. The odorant receptors that lie upon the tufts comb the air for odours, and when a population of olfactory receptors capture their favoured odorant the receptor triggers a chain of enzymatic events that ultimately causes the opening of another type of sodium channel. Thus the olfactory receptor neuron first detects odours through the binding of odorant to its battery of receptors, and then converts this chemical signal into an electrical signal that can eventually be received and interpreted by the olfactory cortex of the brain. When odorant binds to a receptor there is a change in the binding energies within the olfactory receptor that leads to the movement of the receptor's internal regions. Through these movements odorant signals cross the plasma membrane where they subsequently reappear as changes in the conformation of the internal regions of the receptor. Here the relative positions of amino acid residues change in the presence of odorant, becoming either freshly exposed or hidden from the view of other cellular proteins. As far as the other blind, but feeling proteins of the cell are concerned, the receptor protein has changed its face and correspondingly the news that it bears, and this change now dictates a fresh set of instructions to the internal messenger proteins of the cell. Consequently a chain reaction of altered enzyme activities occurs within a key second messenger pathway of the olfactory receptor neuron that eventually results in the opening of a population of sodium channels within the membrane of olfactory receptor neuron. Therefore, within a single sensory neuron a chemical signal has been sampled and turned into one that is electrical. The evolution of the olfactory receptor has enabled chemical information to be discriminated, sampled and converted into the universal language of the nervous system - changes in electrical potential. The odorant receptor functions as both a sensor and a transducer, and there can be little doubt that the odorant receptor is the finest example of nanotechnology in action.

So what type of protein does the intracellular face of the odorant receptor talk to, and what gain is there to be had in switching from a receptor that contains an integral ion channel to one that acts through a series of go-betweens? A one step process such as the opening of an integrated ion channel means that one receptor opens just one ion channel. In contrast the olfactory receptor takes a different road and activates a 'G-protein'. G-proteins are the universal signal amplifiers of the molecular world, translating the atomic motion within activated receptors into changes in the energy stored within chemical bonds, enhancing the signal much as an acoustic amplifier makes a guitar string audible within a packed concert hall. G-proteins, discovered by the legendary Nobel laureates Martin Rodbell and Alfred Gilman, are in essence a kind of 'chemical switch' which couple receptor signals at the cell membrane with biochemical processes that take place deep within the cell, serving in essence as a molecular bridge for a dynasty of receptors that span the membrane seven times in all. When activated the odorant receptor triggers nearby G-proteins to exchange their bound cargo of guanosine diphosphate (GDP) for guanosine triphosphate (GTP) upon their 'alpha' subunits. The nucleotide GTP differs from GDP in that it contains an extra phosphate molecule and therefore an additional high energy bond between phosphates and serves as an essential building block used in the synthesis of DNA. The bulky presence of this additional negatively charged phosphate group, bound deep within the heart of the alpha subunit, commands a change in the conformation of the protein subunit, causing a molecular separation of the alpha subunit from its partner beta and gamma subunits. Once separated the alpha and beta-gamma components go their separate ways to form a forked signalling pathway, each molecule attending to its own duties until another built-in time switch, this time within the alpha subunit causes the third phosphate of GTP to be cleaved, returning the alpha subunit to its inactive GDP-bound state. The inactivated alpha subunit then reassociates with any stray beta-gamma subunits that it can find, and once their union is rejoined the G-protein has returned to its resting conformation in readiness for another cycle.

What then is, or are, the molecular targets for the G-protein's migrant and 'active' alpha subunit? The answer to this question in the olfactory receptor neuron is adenylate cyclase, an enzyme that mass produces the second messenger molecule cyclic adenosine monophosphate (cyclic AMP) by catalysing the formation of a ring-like structure from the cell's reservoir of ATP. Adenylate cyclase reflects the essence of many second messenger pathways in that it converts the common metabolic building block ATP into a short-lived messenger molecule that is itself a highly specific and carefully regulated signal, the whole transformation occurring through a single metabolic step. This is nowhere more elegantly demonstrated than in the conversion of the linear structure of ATP into the ring-like structure of cyclic AMP, the entire process being driven by the liberation of the energy stored between phosphate molecules in ATP. In response to the binding of an odorant the concentration of cyclic AMP increases within the olfactory receptor neuron and binds to the intracellular face of an ion channel which serves as the molecular sensor of the ambient concentration of cyclic AMP, and therefore odorant. The ion channel is thus the end point of the signalling pathway, and represents the final step in the process of converting changes in odorant concentration into changes in membrane potential that the nervous system can utilise.

So why doesn't the odorant receptor simply activate the ion channel directly and cut out the energy consuming middle men from the business of detecting odours, along with all the delay and expense that goes with them? The answer to this piece of evolutionary wisdom lies in the remarkable amplification of the receptor signal that takes place through the various elements of the G-protein cascade. Each receptor that binds an odorant molecule in turn stimulates hundreds of G-proteins for the duration that odorant is bound to it, and each adenylate cyclase enzyme that is stimulated by a G-protein generates hundreds of cyclic AMP molecules for each second of its active lifetime. This staggering amplification causes an increase in cyclic AMP levels that is thousands times greater than the prevailing change in the concentration of odorant, a signal which is sufficient to open many hundreds of ion channels rather than the one integral channel that is opened by an electroplax acetylcholine receptor. The resulting depolarisation is enough to cause an increase in neurotransmitter release from the terminal of the olfactory receptor neuron which we perceive as a smell. If each odorant molecule only activated one ion channel, then the tiny traces of odorant within our environment that signal food or danger would be invisible to our impoverished sense of smell.

So why doesn't cyclic AMP simply continue to accumulate inside the olfactory receptor neuron resulting in a lingering sense of smell? Molecules talk to one another, not just in rigid linear pathways like troops lined up along a World War I trench. They talk with considered pauses, and feedback messenger molecules leave the trench to inform the originator of the message that it has been clearly received and understood. Indeed without such feedback, no complex system for the integration of information could function efficiently. In the olfactory receptor the role of feedback messenger is undertaken by the beta-gamma subunits, the migrant partners of the alpha subunits. This lone pairing of proteins activates another feedback messenger, a G-protein receptor kinase, whose duty it is to inform the olfactory receptor to stop stimulating further G-proteins, a task it achieves by the transfer of phosphate molecules onto the odorant receptor itself, a process known as phosphorylation. The addition of this bolus of negative charge directs the receptor towards its inactive, or 'red light' conformation, but just to tidy up affairs, it would seem only sensible after the departure of the odorant molecule to terminate the cyclic AMP signal as well. Just as cyclic AMP was created in a single step by cleaving a bond between the first and second phosphate molecules of ATP, so in a single step it is then converted from a ring structure back into a more linear one in the form of its cousin adenosine monophosphate (AMP), from which the ATP supply can subsequently be regenerated. The enzyme responsible for cleaving the phosphate bridge that maintains the ring structure is known as a phosphodiesterase, an enzyme that mediates the reverse step in this 'dead-end' pathway. In terms of their atomic make-up, AMP and cyclic AMP are almost identical, but only the latter has substantial second messenger activity in opening the receptor's sodium channels, illustrating the great importance of structure, or stereochemistry in determining the biological activity of molecules.

Odorant detection by the olfactory receptor neuron is just one of many cellular processes that are regulated by cyclic AMP, and cyclic AMP is only one of many second messengers whose levels are in some way governed by G-proteins. The fasting hormone glucagon, adrenaline, the luteinising and follicle-stimulating hormones that control mammalian reproductive cycles and the calcitonin and parathyroid hormones which regulate bone metabolism are but some of the many hormone-receptor systems that employ G-proteins and cyclic AMP to amplify receptor signals. However, in contrast to the olfactory receptor neuron, in many of these different types of cell cyclic AMP binds to an enzyme rather than an ion channel, and this enzyme goes by the name of protein kinase A. Two molecules of cyclic AMP bind to protein kinase A, causing the liberation of active kinase subunits which then transfer phosphate molecules from ATP onto a number of target enzymes and proteins, further amplifying and spreading the receptor's signal. Yet a significant part of the puzzle is still missing. Hormones such as glucagon and insulin compete with one another to establish the balance of cellular activity within many signalling systems, but so far G-proteins have been mentioned only in the context of increasing second messenger levels, where one species of G-protein, known as Gs, acts to increase adenylate cyclase activity. However, without ying there cannot be yang, as all life is a balance of opposing forces. In order to mediate the balance between antagonistic hormones another class of G-proteins evolved to inhibit adenylate cyclase, and this contrary species of G-protein is known as Gi. Thus each class of G-protein is in turn regulated by a distinct triad of hormone, receptor and G-protein. In consequence the cell's response to hormones is determined by what amounts to a see-saw mechanism, where the prevailing concentrations of hormone and the relative numbers of receptors collaborate to determine the balance of cellular activity.

Nowhere is this fine regulatory balance more dramatically illustrated than in the intestine. The single layer of epithelial cells that lines the small intestine is capable of both the net secretion and absorption of salt and water, a balance that is kept in check by the graded release of various hormones and transmitters from the terminals of the intestine's enteric nervous system. Hormones that increase cyclic AMP levels within these intestinal epithelial cells favour a balance of salt and water secretion over absorption, whilst hormones that act by decreasing cyclic AMP levels favour absorption. A delicate balance of cyclic AMP elevating and depressing hormones compete to regulate the ebb and flow of the intestinal tide, a balance which is lost with fatal consequences in the inherited disease Cystic Fibrosis, where there is insufficient secretion to support the proper absorption of fluid and nutrients, and also in infectious diarrhoea where the body becomes dehydrated through the uncontrolled loss of salt and water from the intestines. Thus the net transfer of salt and water across the intestine is the outcome of a fine interplay between the contradictory processes of absorption and secretion, a balance of hormonal signalling that is effectively integrated at the molecular level by adenylate cyclase.

Watery diarrhoea may be induced by bacterial or viral infection and is due to the 'hypersecretion' of salt and water across the surface of the intestine, a condition that accounts for the deaths of some five million children a year through dehydration. Two of the principle bacterial culprits responsible are cholera and Bordetella pertussis, both of which produce toxins that effectively hijack the cyclic AMP second messenger system of the intestinal epithelial cells. Their toxins sabotage the balance by persistently activating adenylate cyclase through the chemical modification of the G-protein alpha subunits that govern cyclic AMP production. Cholera toxin irreversibly modifies the alpha subunit of Gs by adding the cellular metabolite ADP-ribose, preventing it from returning to its quiescent state, resulting in a 'runaway' production of cyclic AMP and the uncontrolled loss of salt and water from the intestine. In a perhaps not so subtle contrast, pertussis toxin modifies and permanently inactivates adenylate cyclase's suppressor Gi through much the same mechanism, thereby preventing it from down-regulating cyclic AMP production with the same devastating consequences. Concentrations of intracellular second messengers are thus a delicate balance set by competing hormonal influences, and as is illustrated by the intestine, a perturbation in the pathways that govern their production may have dramatic (and fatal) consequences.

Receptors that talk to the cell through G-proteins are termed metabotropic receptors because they directly influence the metabolic status of the cell. G-proteins have been shown to govern a great number of cellular processes including the contraction of smooth muscle cells, the control of glycogen reserves in liver cells, platelet aggregation in blood vessels and the secretion of inflammatory mediators by mast cells. The control of such a diverse number of cellular processes is achieved not only through the modulation of ion channels and adenylate cyclase, but also through other second messenger generating enzymes. In his book the Extended Phenotype, Professor Richard Dawkins refers to the meme, which he defines as a cultural or technological theme that becomes self-perpetuating in a society simply because it is a good idea. Biological systems of interacting genes, such as those that form G-protein signalling systems have similarly been preserved throughout evolution because they provide a simple and effective biochemical strategy for the amplification of signals. Consequently G-protein systems are ubiquitous, regulating all manner of systems from intracellular cellular calcium levels to the direct regulation of ion channels, and the list of processes known to be controlled by G-proteins grows ever larger with investigation. The advent of the G-protein switch represented a quantum leap in evolution, an advance that allowed small signals to become greatly amplified, endowing us with otherwise unimaginable levels of acuity in our senses of vision, smell and taste.

So we have now identified two receptor mechanisms, one for the fast, localised transmission of information in nerves and muscle, and another for the graded amplification of signals that are carried by otherwise undetectable levels of hormone. Two quite different problems of information transfer that were solved by two intriguingly different strategies, demonstrating once again that time and Nature are the greatest engineers. Yet one further problem of information transfer remains unelucidated. Many cellular processes such as growth and division, regulated by the family of hormones known as growth factors, take place over many hours or even days, demanding co-ordinated changes within the cell's many diverse metabolic and signalling pathways. Whereas a receptor that governs the opening of an ion channel or the activity of a G-protein may elicit a brief and highly localised change in the activity of the cell, the nature of a receptor that governs long-lasting changes in both the expression of the cell's genetic programme and its metabolic and structural machinery is likely to be very different. Clearly such a receptor signal must be not only be amplified, but also spread widely through the cell to co-ordinate such complex changes in activity. In fact this class of receptor communicates through not just one, but indeed several distinct second messenger pathways that serve to disperse the receptor signal.

Growth hormone is one of the best known of the growth factors, promoting bone growth and increases in body cell mass making it useful in the clinical correction of growth deficiency in those children who produce insufficient quantities of this hormone. At the level of cell metabolism, growth hormone increases the 'burning' or oxidation of fats for fuel and also increases the uptake of amino acids into cells for the synthesis of proteins. These combined actions of growth hormone result in an increase in lean body mass and a decrease in body fat, a panacea for weight watchers and foolhardy bodybuilders alike. Remarkably, growth hormone acts through the same receptor to stimulate a number of different cellular processes that include changes in gene expression, cell growth through synthesis and division, an increase in the uptake of glucose and amino acids into the cell and elevations in the levels of calcium ions within the cell. Through the wizardry of molecular biology we now even know the precise internal clusters of amino acids of the growth hormone receptor that are responsible for each of these signalling functions. Growth hormone is but one of many hundreds of growth factors, all sharing a similar strategy for the dispersal of information within the cell.

So how do we find a helpful pattern from such an apparent diversity, where hundreds of different growth factors and their receptors have been identified, and just one growth factor receptor has taken hundreds of human working years to decipher? As demonstrated by the 'molecular meme' of the G-protein, a good idea can be used a thousand times with only subtle refinements, and that which is essentially required to achieve fine control over the growth and specialisation of the many specific populations of cells within the body is the use of a different lock and a different key to open it. Mother evolution and father time have conspired to create a language of different growth factors, each acting through their own tailor-made receptors which are only found upon a unique subset of cells.

Perhaps surprisingly growth factor receptors possess a strikingly simple structure, in stark contrast to the complex membrane criss-crossings and internal foldings of receptors which act through ion channels and G-proteins. The subunits of growth factor receptors in fact span the membrane only once, a simple structure that betrays a simple function. Growth factor receptors are essentially membrane scaffolds for the assembly of an elaborate protein collage from which a diversity of second messenger pathways spring, dispersing the hormone's information throughout the cell. Growth factor receptors have a top, a middle and a bottom, and are in some ways reminiscent of an angler's float. A single portion of the receptor breaks the surface, projecting upwards, waiting, listening for twitches in the angler's line. Multiple hooks, each with a unique bait, dangle beneath the surface of the membrane providing tantalising points of entrapment for various choosy fish. The 'top' of the growth factor receptor projects from the surface of the cell, recognising and binding to the growth factor of choice; its mid-region spans the cell membrane, serving to translocate the hormone's signal into the cell, whilst its 'bottom', or intracellular region provides the scaffolding for the attachment of the various signalling pathways that pass the hormonal message to the machinery of the cell. But before we can appreciate how the various regions of the receptor suddenly become active upon binding to growth factor, we must first fully understand an element of the essential grammar of cell signalling - protein phosphorylation.

Growth factor receptors are, however, not quite as inexcitable as at first they might appear. In addition to their role in protein scaffolding they are members of the family of protein kinases that includes protein kinase A and the G-protein receptor kinase whose acquaintance we have already made. However, unlike protein kinase A which phosphorylates the relatively small amino acids serine or threonine, the kinase region of the growth factor receptor transfers the terminal phosphate of ATP onto exposed side chains of the much bulkier amino acid tyrosine. Yet only a fraction of the exposed threonine and serine or tyrosine residues are phosphorylated, as protein kinases only transfer phosphate onto those amino acids that are surrounded by a specific recognition sequence, just as a blazer will not gain admission into the Marylebone Cricket Club pavilion without a club tie. Indeed without such a recognition code, protein kinases would indiscriminately transfer phosphate onto all the exposed serine, threonine or tyrosine residues, and the information carried by the receptor would disperse senselessly in the crowd. As importantly, the transfer of negatively charged phosphates to and from cellular proteins provides a simple molecular 'on-off' switch by which many cellular processes are controlled, and these key control proteins are marked by an appropriate recognition sequence, a form of Masonic handshake that separates a protein from the crowd.

Growth factor receptors are tyrosine kinases, and tyrosine phosphorylation is the hallmark of growth factor signalling pathways. Protein phosphorylation dramatically alters interactions both within and between target proteins, changing both their conformation and consequently their activity. Once the lock has met the key, and the receptors have bound their growth factors they immediately pair off as bonded couples, albeit same sex marriages, and as part of this molecular marriage ceremony they phosphorylate one another at one or more tyrosine residues. Once paired and mutually phosphorylated, the required framework for the signalling scaffold is in place. However, activated growth factor receptor tyrosine kinases don't stop there, and they continue to phosphorylate tyrosine residues upon other nearby target proteins, including other protein tyrosine kinases. Many of these proteins bearing phosphorylated tyrosines subsequently become associated with the receptor scaffolding, and by this strategy growth factor receptors gather other nearby proteins into their hive of activity, and signalling pathways consequently become assembled and activated around the nucleus of the receptor scaffold. To use a colourful analogy, growth factors instigate an avalanche of tyrosine phosphorylations leading to the activation of a number of signalling cascades involving dozens of other types of protein.

However, the first step in the passage of the activated growth factor's instructions into the cell involves the association of the primary 'anchor' proteins of each of the principal signalling pathways with the tyrosine phosphorylated receptor scaffolding, a process that occurs rather like a form of molecular 'sticky velcro', where the phosphorylated tyrosines behave like a series of tiny hooks that hold the entire molecular collage in place. The metaphorical 'loops' in this sticky protein velcro assembly are provided by specialised regions within proteins that specifically recognise these phosphorylated tyrosine 'hooks'. These loop regions are known as SH2 domains, and are found upon many proteins involved in growth factor signalling. Add to this a second type of 'sticky' region, formed by SH3 domains that recognise and bind to regions upon neighbouring proteins which are rich in the amino acid proline like the 'Tec' protein domain, and it is perhaps not hard to imagine how such a clustering of 'like-minded' proteins occurs upon the growth factor receptor scaffolding once the critical event of receptor tyrosine phosphorylation has occurred. These assemblies of signalling proteins upon the activated growth factor receptor scaffolding allows the information carried by the growth factor to be dispersed widely throughout the cell by the parallel activation of several signalling pathways, much as the Nile disperses its waters at its delta. By their very nature growth factor receptors orchestrate many processes within the cell, but to fully understand them we must first elucidate the actions of the individual signalling pathways that they recruit, or at least we do if we are to appreciate why cancers develop, or how HIV causes such massive T-cell losses during AIDS.

Growth factors are of critical importance in both development and disease, and many serious and lethal conditions are now being associated with a failure of their action. For instance, abnormally low levels of growth hormone in humans cause dwarfism, and mice that have had the gene that encodes for Nerve Growth Factor disrupted lose large numbers of their neurons and die prematurely. Nerve Growth Factor, or NGF to its closest admirers, is a member of the family of 'neurotrophic' growth factors that regulate the growth, wiring during development and survival of neurons, and has become an intensely scrutinised model for our understanding of the mechanisms of growth factor signalling. Once again the sharp scalpel of molecular biology has come to our aid, allowing us to appreciate the structure and function of the NGF receptor. Through an ingenious series of deductions we know that the activated NGF receptor uses its phosphorylated tyrosines to recruit at least three primary 'anchor' proteins that bear SH2 loops onto the receptor scaffold. One of these, a protein called SHC, communicates with the nucleus via an avalanche of protein phosphorylations after it has activated a member of the small G-protein family known as ras. The second is the enzyme phospholipase C, whose activation causes the release of a messenger stored within the membrane that increases calcium levels within the cell; and the third anchor protein is another central player in the control of growth and division, the enzyme 'phosphatidyl-inositol 3-kinase', or '3-kinase' to its friends. By deleting each of the tyrosine residues that anchor these three primary proteins in turn, molecular biologists have cleverly determined the role of the ras, the 3-kinase and phospholipase C signalling pathways in regulating the cell's response to growth factors. In referring to them as the ras, 3-kinase and phospholipase C signalling pathways we are somewhat oversimplifying matters, as each of these enzymes represents but one step within a cascade of enzyme signalling events. However these enzymes are of central importance in each of these signalling pathways, as they represent the rate limiting steps within each pathway, and without them, and it is possible to selectively delete each in turn, the cellular response to a receptor signal 'downstream' of the deleted enzyme is greatly diminished. Thus these three primary anchor proteins represent the firing pin of the rifle, a little click that triggers a much larger explosion of events that can be seen as a change in the activity and behaviour of the cell.

So what do each of these three growth factor pathways tell the cell to do, and how were they discovered? Cancer is a family of diseases related to the failure to control the rate of cell division. Cancerous cells become antisocial and often fail to specialise, or differentiate, preferring instead to carry on dividing regardless of cues from inhibitory growth factors and contacts with neighbouring cells. The careful study of cancer cells revealed that a great number of proteins become altered, or mutated, so that they no longer transmitted a carefully regulated signal for growth and division to the cell, and perhaps not surprisingly these proteins were found to be growth factors, receptors or signalling proteins at the level of the anchor proteins and beyond. These altered proteins became known as oncogenes, and their discoverers Michael Bishop and Harold Varmus, Nobel Laureates. Depending upon the type of cell concerned and the state in which the growth factor finds it, ras and its beholden cohorts of protein kinases promote the growth, survival and progression of the cell towards the point where it divides into two daughter cells. The remarkable feature of the ras pathway is the extent to which amplification of the signal occurs, a feat achieved again by the fact that ras is a G-protein. A single NGF receptor activates many ras G-proteins through an GTP exchange factor that is itself moored in turn to the receptor through SHC. Each activated ras protein then activates a protein kinase known as raf. From this point on, the signal heads towards the nucleus and the DNA through an avalanche of tyrosine and threonine/serine phosphorylations, causing a stepwise amplification of the signal, rather as a director's communiqué progresses to the workers with ever more messengers recruited at each level in the chain of command. Finally the ras signalling avalanche activates special nuclear proteins known as transcription factors, whose role it is to trigger the copying of specific regions of the DNA master code into its messenger form, RNA, by phosphorylating them. These messenger RNA molecules, each an identical replica of a gene, are then exported from the nucleus and translated into the various proteins which they encode. As the function of the cell is defined by its complement of proteins, each set of transcription factors that is activated will in turn subsequently redirect or in some way modify the activity of the cell, because the expression of each set of genes lies under the control of a different transcription factor, in much the same way as different military divisions lie under the direction of different generals. Although the ras, 3-kinase and phospholipase C pathways are each capable of altering patterns of gene expression and cell activity independently, it is customary for different generals and their battalions join forces to wage a campaign, and as is often the case the outcome of the battle amounts to substantially more than the sum of the divisions.

Transcription factors direct the expression of the message encrypted within the genes, and the gene is itself the fundamental messenger of the cell, and indeed of life. Genes are encoded within the DNA that is wound into the coils that form the chromosomes, but for the DNA message to manifest itself it must first be expressed in its messenger form, RNA. Messenger RNA is related to DNA as a floppy disc is to the hard drive of a computer, and is free to leave the nucleus carrying the instructions for proteins. However, for the genetic message to be realised, messenger RNA must first be translated into its protein form, a transformation that takes place within a network of membrane passageways that branch out from the nucleus and into the cell's salty matrix. The innermost regions of these interconnected membrane passageways are studded with protein complexes that serve as RNA reading devices, known as the rough endoplasmic reticulum after their appearance. In the rough endoplasmic reticulum the message is read and converted into the protein specified by the gene, with an accuracy as unerring as the copying of a program file from a floppy disc onto a computer. Once formed the section of membrane containing the newly formed proteins buds off from the surrounding membrane and is transported further out into the network of membrane passageways and foldings to a processing factory known as the Golgi complex.

This transfer of information from DNA to RNA and finally to protein represents the most fundamental and universal of signalling pathways. Genes encode specific proteins, and specific proteins have specific functions. Cells from the pancreas, liver, heart and brain differ because different portions of their identical DNA inheritance are manifested in the form of proteins at different stages during development; and even within a certain type of cell, this pattern of expression varies further with changes in the cell's environment. A biological trinity can be said to exist, as the genes (DNA), their message (RNA) and the proteins that they encode are one and the same, yet different, separated in their influence by time. To draw another analogy, a cell is like a computer connected to the internet. The computer has access to all programs available in 'cyberspace', that limitless inter-relating network of communicating computer memory, but until that program is summoned, copied and operated upon a user station, the program is distant, silent, merely possessing the potential to perform a task. Programs that operate upon the workstation can be said to be active, and those stored remotely in cyberspace are not, and so it is the computer station user who defines the set of programs that are in operation and thereby the function of the workstation. Another user possessing an identical computer may have access to the precisely the same set of programs through the internet, but is likely to summon a different set of programmes into active service, thereby conferring an entirely different function upon the workstation. Much the same is true of cells and DNA. Cellular cyberspace may thus be regarded as the huge volume of genetic information encoded within the DNA, and the hormonal influences of development and the environment are the station's users, acting through receptors to direct the expression of different sets proteins (the cellular equivalent of programmes), thereby defining the both cell and its vital function.

In conclusion, in growth factor signalling pathways second messengers are generated through primary enzymes, such as the 3-kinase, ras or adenylate cyclase, and serve to alter the activity of key enzymes that lie further 'downstream' of the receptor signal. These key enzymes are the origins of the signal deltas in the river of information flow, the point at which the information is dispersed throughout the cell. The branch point of the delta may be a protein kinase activated by a second messenger such as protein kinase A, or alternatively it may be another protein that changes its shape and activity upon binding to a second messenger, such as the protein calmodulin which communicates increases in cellular calcium levels to a set of otherwise insensitive proteins. Each of these key enzymes has its own dominion of proteins subject to its influence, although some may be governed by more than one receptor overlord. Key enzymes carry an all points bulletin, and all processes which contain a protein with a sequence that recognises the key enzyme change their activity accordingly. Often a number of apparently unrelated enzymes, ion channels and structural proteins within the cell respond to a key enzyme, and each of these responsive proteins is necessary for a co-ordinated cellular response to a hormonal signal to occur.

An analogy may be drawn between the response of a cell to a hormone and the response of a company to a change in the market. Efficient and effective communication is key, and the co-operation of all departments involved is essential for the successful execution of any corporate plan. Let us imagine the cell as a company that provides a certain range of products for the economy. The company director is the DNA, possessing a detailed knowledge of the full range of products that the company can produce, and the director's office is the hub of operations (the nucleus). Proteins, the metaphorical company workers, are found compartmentalised within their respective areas of production (the cellular compartments), with the notable exception of the mail men and secretaries (the second messengers) who pass freely between departments. An incoming facsimile from the sales force (a hormone or transmitter) is received by the fax machine (the receptor), and if it is within current production capacity is sent via the junior managers (the receptor-operated G-protein and ion channel pathways) or executive managers (such as adenylate cyclase) who directly commission the production and release of product (for example the release of neurotransmitter, muscle contraction or fluid secretion). However, where larger, longer term and more strategic orders are concerned, and a major investment of resources seems likely to be required (involving a heavy consumption of ATP and metabolic resources). Accordingly, more senior executives are then advised (phospholipase C, ras and the 3-kinase) who then inform the staff in the director's office (the transcription factors) who then confer with the director (DNA) who then issues appropriate directives (in the form of messenger RNA) commissioning more executives, managers and workers (the synthesis of new sets of proteins) for the purpose of reorganising the workforce (changing the patterns of protein expression), restructuring company production (cell differentiation), or if the order is sufficiently large to warrant company expansion, the formation of a daughter company (cell division occurs). In many ways cells respond to their environment much as a company responds to the market place. If the company does not listen to the signals from the market it runs the risk that it will not survive in the competition for resources, and much the same is true for cells as can be seen in the fate of unfit spermatozoa and misguided neurons.

And so to the grand view. All incoming signals must traverse the membrane in order to transfer their message on to the workings of the cell, and to this end Nature has evolved three general strategies by which fat-insoluble signals cross the cell membrane. By combining an external receptor site with an ion channel Nature has created the millisecond message, where changes in hormone and transmitter levels are rapidly turned into highly localised electrical signals which allow information to be readily generated and dispersed in large and complex animals, a development essential for survival in a cruel, competitive world. More widespread and gradual responses within the cell necessitated the evolution of more elaborate receptor mechanisms. These appeared in the form of G-protein amplifiers and receptor tyrosine kinases which orchestrate cell differentiation, growth and division in response to growth factors. Yet assimilating information is a costly business, as anyone who has recently returned from a concentrated afternoon in the Tate or Louvre will tell you. The constant bombardment with sensory information, whether it be in an art gallery, stock exchange or convention hall, saturates the signalling pathways of the mind and leads to the consumption of large amounts of energy that is stored within ATP and GTP through the activity of kinases, G-proteins and ion pumps. For as any well-heeled individual in society knows, keeping abreast of affairs requires time, resources and energy.