Introductory Review Cellscience Reviews Vol 1 No.3 ISSN 1742-8130

L-type Calcium Channel Regulation of Neuronal Gene Expression

Jason P. Weick, Sidney P. Kuo & Paul G. Mermelstein

Introduction

From fertilization to programmed cell death, signaling cascades triggered by increases in intracellular calcium are vital to the cellular processes of life. Underscoring the importance of calcium signaling is its central role in activity-dependent gene expression. Calcium-mediated gene expression is the principle link between extracellular cues and enduring changes in cell function, as modification of protein synthesis underlies such diverse processes as cell survival, differentiation and synaptic plasticity (Ghosh et al., 1994, McAllister et al., 1996, Brosenitsch et al., 1998, Mao et al., 1999, Kandel, 2001). Alterations in intracellular calcium may influence various stages of gene expression, including mRNA elongation, splicing, stability and translation (Finkbeiner and Greenberg, 1998, West et al., 2001). However, since transcriptional initiation is of fundamental importance to changes in gene expression, considerable effort has been put forth to understand the influence of calcium on the regulation of various transcription factors.

Work over the past two decades has revealed that a specific subpopulation of voltage-gated calcium channels play a privileged role in activating gene expression in multiple cell types. Calcium entry specifically through L-type calcium channels is important for transcriptional responses in muscle, pancreatic ß-cells, osteoblasts and neurons (Schwaninger et al., 1993, Cartin et al., 2000, Porter et al., 2002, Bergh et al., 2004, Spangenburg et al., 2004, Wamhoff et al., 2004). Not surprisingly, naturally occurring mutations of L-type calcium channels can lead to a variety of cellular and organ dysfunctions including cardiac arrhythmia, immune deficiency, congenital heart disease and abnormal brain function (Splawski et al., 2004). Specifically in brain, L-type calcium channels have been implicated in mediating long term changes in neuronal activity (Grover & Teyler, 1990, Wickens & Abraham, 1991, Bolshakov & Siegelbaum, 1994, Bi & Poo, 1998, Kapur et al., 1998, Morgan & Teyler, 1999, Weisskopf et al., 1999) and modulation of behavior (Borroni et al., 2000, Cain et al., 2002, Shinnick-Gallagher et al., 2003, Zhang et al., 2003, Barad et al., 2004, Licata et al., 2004, Suzuki et al., 2004). In this review, we focus upon changes in gene expression in nerve cells of the mammalian brain in order to highlight the role of L-type calcium channels in regulating long-term changes in cell function.

Localized Calcium Signaling and L-type Calcium Channel-Dependent Gene Expression

In most neurons, multiple mechanisms exist whereby increases in intracellular calcium concentrations may occur. These include calcium entry through ligand-gated receptors, such as N-methyl-D-Aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) glutamate receptors, various voltage-gated calcium channels, as well as the release of calcium from intracellular stores (Ghosh et al., 1994, Geiger et al., 1995, Berridge, 1998). Upon heightened periods of neuronal activity, each of these processes may contribute to the overall rise in intracellular calcium. Therefore, blockade of L-type calcium channels under stimulus conditions that trigger gene expression often results in only a small reduction in total calcium influx. However, eliminating calcium entry through L-type calcium channels disproportionally suppresses the transcriptional response (Murphy et al., 1991, Deisseroth et al., 1998). This privileged role of L-type calcium channels in gene expression has been observed in many neurons, including those found within the hippocampus, cortex, striatum, retina, dorsal root ganglia and cerebellum (Murphy et al., 1991, Bading et al., 1993, Yoshida et al., 1995, Liu and Graybiel, 1996, Ai et al., 1998, Cigola et al., 1998, Genazzani et al., 1999, Rajadhyaksha et al., 1999, Redmond et al., 2002, Sanna et al., 2002). Thus began the mystery as to how neurons are able to discriminate the route by which calcium enters the cytosol, initiating changes in gene expression only when L-type calcium channels become activated.

Early studies examining the distribution of α1C (CaV1.2) and α1D (CaV1.3), the two principal pore-forming subunits of L-type calcium channels expressed in neurons, found them to be primarily restricted to the cell soma and proximal dendrites where they seem poised to trigger nuclear responses (Ahlijanian et al., 1990, Westenbroek et al., 1990, Hell et al., 1993, Westenbroek et al., 1998). However, P/Q-, R- and N-type calcium channels also display somatodendritic localization and contribute significantly to somatic calcium channel currents (Mintz et al., 1992, Scroggs & Fox, 1992, Westenbroek et al., 1992, Hoehn et al., 1993, Bargas et al., 1994, Eliot & Johnston, 1994, Guenther et al., 1994, Lorenzon & Foehring, 1995, Randall & Tsien, 1995). Therefore, it is not simply the relative strength of the calcium signal generated by L-type calcium channels or their proximity to the nucleus that accounts for their privileged signaling abilities. What then, is the primary mechanism by which L-type calcium channels are linked to gene expression, to the exclusion of other calcium entry routes?

Studies on L-type calcium channel activation of the transcription factor cAMP Response Element Binding protein (CREB) have yielded significant insight into this question. CREB has been widely examined due to its important role in activity-dependent plasticity, underlying diverse functions such as circadian rhythms, drug addiction, hyperalgesia, and learning and memory (Silva et al., 1998, Lonze & Ginty, 2002). While phosphorylation of a number of residues may regulate CRE-dependent gene expression (Gau et al., 2002, Kornhauser et al., 2002), phosphorylation of serine 133 (Ser133) is essential for CREB activation (Deisseroth & Tsien, 2002). In neurons, depolarization-induced CREB phosphorylation of Ser133 is primarily mediated by two pathways with different temporal kinetics (Figure 1). Calcium influx initially recruits the actions of a fast CaM kinase IV (CaMKIV)-dependent pathway (Bito et al., 1996, Ho et al., 2000, Kang et al., 2001) followed by a slower, mitogen activated protein kinase (MAPK) signaling pathway (Impey et al., 1998, West et al., 2001, Wu et al., 2001). Both pathways require calcium binding to calmodulin (CaM) (Deisseroth et al., 1998, Impey & Goodman, 2001, Wu et al., 2001).

Recent evidence suggest that local calcium signaling, in close proximity to the point of calcium entry, affords L-type calcium channels the specificity to activate CaM-mediated CaMKIV- and MAPK-dependent CREB phosphorylation. A study by Deisseroth et al. utilized different calcium chelators to determine the spatial signaling requirements of calcium-dependent CREB phosphorylation. When cells were loaded with BAPTA, a chelator with high affinity and capacity, depolarization-induced CREB activation was eliminated. Compared to BAPTA, the calcium chelators EGTA and Br2-BAPTA exhibit slower binding kinetics and reduced affinity, respectively. And while EGTA and Br2-BAPTA eliminated bulk cytosolic calcium transients in response to stimulation, CREB phosphorylation was unaltered (Deisseroth et al., 1996). These data suggest that micromolar calcium concentrations near the mouth of the L-type calcium channel (~1μm) are necessary to trigger CREB phosphorylation. But in fact, recent studies suggest that the observance of differential effects between BAPTA and EGTA upon calcium signaling results from “nanodomain” signaling (Augustine et al., 2003). Modeling of localized calcium through voltage-gated calcium channels indicates that the ‘functional window’ for activation of proteins such as CaM may be within 100-200nm of the point of entry, where calcium concentrations are 100- to 1000-fold higher than ‘bulk’ cytoplasmic concentrations (Yamada & Zucker, 1992, Naraghi & Neher, 1997). Moreover, additional evidence for localized calcium signaling arose from imaging experiments that measured somatic calcium concentrations under conditions in which CREB phosphorylation was triggered following a modest depolarization. Specifically, CaMKIV-dependent CREB phosphorylation following a three-minute application of 20mM K+ occured when peak cytosolic calcium concentrations averaged only 150nM (Weick et al., 2003), far below the Kd (10μM) for calcium binding to calmodulin (Van Eldik & Watterson, 1998). These data further suggest that a highly localized calcium signal is principally responsible for L-type calcium channel activation of CREB.

Structural Requirements of L-type Calcium Channels to Regulate CREB

Further refinement of the localized signaling model has been derived from a series of papers examining interactions of the L-type calcium channel with both CaM and structural proteins. A recent study by Dolmetsch et al. demonstrated that deletion of the CaM-binding ‘IQ motif’ region from α1C results in L-type calcium channels that are unable to trigger MAPK-dependent CREB phosphorylation and CRE-dependent transcription (Dolmetsch et al., 2001). Thus, L-type calcium channels contain an inherent structural requirement in order to signal changes in gene expression. However, the interaction of CaM with L-type calcium channels cannot fully explain their privileged ability to trigger changes in gene expression, as other α1 subunits contain analogous IQ motifs (Lee et al., 1999, Peterson et al., 1999). Furthermore, CaM appears constitutively anchored to the IQ motif, regulating calcium-dependent inhibition or facilitation (Peterson et al., 1999, Zühlke et al., 1999, Zühlke et al., 2000), and thus indirectly suppressing or augmenting activity-dependent gene expression.

In addition to the IQ motif, the C-termini of both α1C and α1D contain unique type I PDZ interaction sequences (Kurschner & Yuzaki, 1999, Bezprozvanny & Maximov, 2001), known to bind various scaffolding proteins that contain PDZ domains (Kurschner et al., 1998, Kurschner & Yuzaki, 1999, Zhang et al., 2005). Interactions between channels and receptors with PDZ domain proteins generate macromolecular complexes which couple related signaling partners (Craven & Bredt, 1998, Sheng & Pak, 2000). Thus, it was theorized that the subcellular distribution of L-type calcium channels, promoted by interactions with PDZ proteins, targets these calcium channels to regions where CREB signaling is initiated. As such, L-type calcium channels would aggregate with the calcium-sensitive second messengers responsible for CREB activation, whereas other calcium channels would be excluded from these same subcellular regions. Consistent with this model, a recent study found that CaM concentrations proximal to L-type calcium channels greatly exceed that of free intracellular concentrations (Mori et al., 2004).

In the initial study to examine the role of PDZ domain proteins in L-type calcium channel-dependent gene expression, localization of α1C-comprised L-type calcium channels was disrupted by overexpression of the α1C PDZ interaction sequence. While not affecting calcium entry through these channels, CREB phosphorylation and CRE-dependent transcription was compromised. Furthermore, L-type calcium channels lacking the α1C PDZ interaction sequence exhibited limited ability to activate CREB (Weick et al., 2003), supporting the notion that a physical association between α1C-comprised L-type calcium channels and PDZ domain proteins is critical for activity-dependent gene expression. Thus far, the α1C PDZ interaction sequence (VSXL) has been demonstrated to bind the PDZ domain proteins CIPP and NIL-16 (Kurschner et al., 1998, Kurschner & Yuzaki, 1999). Both CIPP and NIL-16 may serve to aggregate L-type calcium channels with accessory proteins that are necessary for CREB activation. However, the disparate and limited expression pattern of CIPP and NIL-16 throughout the brain suggests there may be other PDZ domain proteins that contribute to the ability of α1C-comprised L-type calcium channels to preferentially signal to CREB.

Recent work from the Bezprozvanny lab has confirmed the role of the PDZ interaction sequence on α1C in mediating L-type calcium channel CREB phosphorylation, and has further demonstrated a similar mechanism by which L-type calcium channels containing the long splice-variant of α1D trigger CREB activation (Table 1). Disruption of α1D-comprised L-type calcium channels with the PDZ domain protein Shank resulted in a diminution of L-type calcium channel-dependent CREB phosphorylation. In this case, α1D-comprised L-type calcium channels interact with Shank via the C-tail PDZ interaction sequence (ITTL) as well as a proline-rich region in α1D that binds the Shank-SH3 domain (Zhang et al., 2005).

Table 1: Both α1C- and α1D-comprised L-type calcium channels regulate CREB activation through interactions with PDZ domain proteins.

With common mechanisms in place for channel localization, α1C- and α1D-comprised L-type calcium channels appear to cooperate to ensure efficient transcriptional activation under a variety of stimulation parameters. Of note, along with somatic localization, recent evidence finds L-type calcium channels within dendritic spines and dendritic shafts, including being localized within synapses (Obermair et al., 2004, Zhang et al., 2005). Possibly, L-type calcium channels work in concert to enhance synaptic stimulation and their own activation, leading to changes in gene expression. Although previous studies have demonstrated initial CaMKIV-dependent CREB phosphorylation occurs on a time scale that places a strict spatial constraint on the localization of L-type calcium channels and CaM to the cell body (Mermelstein et al., 2001), opening of L-type calcium channels within dendritic regions would support depolarization and activation of L-type calcium channels proximal to the soma.

Interestingly, not all types of electrical stimulation are capable of triggering L-type calcium channel gene expression. While there are notable exceptions (Fields et al., 2001, Dudek & Fields, 2002), in many systems action potentials in the absence of synaptic activity are insufficient to produce activity-dependent gene expression (Chalazonitis & Zigmond, 1980, Luckman et al., 1994) and L-type calcium channel-mediated CREB phosphorylation (Bito et al., 1996, Deisseroth et al., 1996, Mermelstein et al., 2000). Reliance upon repeated synaptic stimulation to trigger gene expression may be a result of the distinct biophysical properties of L-type calcium channels. Relatively slow activation kinetics as well as activation at relatively hyperpolarized potentials (in some cases, the voltage-dependence of α1D-comprised L-type calcium channels exhibits a pronounced (~20mV) leftward shift in activation) allows these channels to act as a kinetic filter, responding only to stimuli meant to trigger changes in gene expression (Randall & Tsien, 1995, Avery & Johnston, 1996, Magee et al., 1996, Mermelstein et al., 2000, Platzer et al., 2000, Safa et al., 2001, Olson et al., 2005).

L-type Calcium Channel Regulation of NFAT-Dependent Transcription

Besides CREB, L-type calcium channels are known to activate a number of other important transcription factors including MEF-2, SRF, NF-κB, and NFAT (Misra et al., 1994, Graef et al., 1999, Mao et al., 1999, Shen et al., 2002). The nuclear factor of activated T-cells (NFATc) was originally characterized in the immune system, but is now known to play an important role in brain function as well (Graef et al., 1999, Graef et al., 2003, Groth et al., 2003, Benedito et al., 2005). A number of important neuronal gene products are regulated by NFAT-dependent transcription and at least one isoform of NFATc, NFATc4, was found to be preferentially activated by calcium entry through L-type calcium channels (Graef et al., 1999). It remains unclear whether the mechanisms that support signaling to CREB also facilitate preferential coupling of L-type calcium channels with other transcription factors. However, significant differences between the activation of CREB and NFATc4 suggest that additional mechanisms may underlie L-type calcium channel regulation of NFATc4, and possibly other, transcription factors.

In contrast to the primarily nuclear localization of CREB in resting neurons, NFATc proteins are localized to the cytoplasm in an inactive, phosphorylated state. Activation of the serine/threonine protein phosphatase calcineurin (CaN, also termed protein phosphatase 2B) following a rise in intracellular calcium leads to dephosphorylation of NFATc, and subsequent nuclear import via unmasking of multiple nuclear localization signals (Crabtree & Olson, 2002, Hogan et al., 2003). Within the nucleus, NFAT binds to DNA to initiate transcription in cooperation with a nuclear partner, generically termed NFATn, which is typically activated by protein kinase C (PKC, Figure 2). In addition to activation of NFATc and NFATn, calcium entry through L-type calcium channels also appears to impede nuclear export of NFATc4, through inhibition of glycogen synthase kinase 3ß (Graef et al., 1999).

Compared to CREB, relatively little is known regarding the mechanisms that support signaling between L-type calcium channels and NFATc4 in neurons. Because CaN influences numerous cellular processes in response to diverse signals (Groth et al., 2003), it seems likely that local signaling events will also be important for specific activation of NFATc proteins. However, disruption of α1C-PDZ protein interactions did not affect NFAT-dependent transcription initiated by calcium entry through L-type calcium channels (Weick et al., 2003), raising the possibility that other structural interactions may be involved in coupling L-type calcium channels to NFAT. One possibility is that interactions between Shank and Homer localize α1D-comprised L-type calcium channels with CaN and inositol trisphosphate (IP3) receptors (Olson et al., 2005) to support NFAT-dependent transcription. Consistent with this hypothesis, NFATc is also activated following IP3 receptor stimulation (Graef et al., 2003, Groth et al., 2003). L-type calcium channels comprised of α1C subunits may also play a role in NFAT-dependent transcription through an association with members of the A-kinase anchoring protein 79/150 (AKAP79/150) family of proteins (Gao et al., 1997, Altier et al., 2002), which may support signaling to both NFATc and NFATn by recruiting CaN and PKC to the local environment of the L-type calcium channel (Coghlan et al., 1995, Klauck et al., 1996, Oliveria et al., 2003). In some ways similar to PDZ domain proteins, the AKAP family is a group of functionally related proteins capable of organizing macromolecular signaling complexes. Future studies will undoubtedly explore whether AKAP79/150 and/or Homer couple L-type calcium channels to NFAT-dependent transcription.

Conclusions

Recent studies investigating activity-dependent gene expression present a clearer picture of the mechanisms in place to support L-type calcium channel regulation of neuronal gene expression. Calcium that enters through L-type calcium channels acts in close proximity to the channel to trigger the signaling pathways leading to a transcriptional response. This local signaling is achieved through assembly of macromolecular signal transduction complexes in which specific calcium-sensitive signaling molecules are maintained within the microdomain environment surrounding the channel (Figure 3). These findings add to the accumulating evidence that neurons rely heavily upon localized signaling to impart specificity to the variety of calcium inputs responsible for diverse aspects of neuronal function (Augustine et al., 2003).

The ability of L-type calcium channels to initiate local signaling events that transmit information to the nucleus allows these channels to play a vital role in long-lasting changes in brain function. By coupling the activity of transcription factors such as CREB and NFAT to membrane activity, L-type calcium channels permit a cell to adapt its functional properties to experience. Studies of CREB and NFAT regulation have significantly contributed to our understanding of the molecular mechanisms underlying enduring changes in neuronal function. Continued investigation by which L-type calcium channels regulate the activity of these and other transcription factors will prove essential to a full appreciation of behavioral processes including learning and memory, and neuropsychiatric diseases including drug addiction, epilepsy, autism, and depression.

Acknowledgements
Work is supported by NS41302 (PGM) and a predoctoral NRSA (JPW). The authors would like to thank Dr. Karl Deisseroth for comments on this manuscript.

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