Introductory Review Cellscience Reviews Vol 2 No.1 ISSN 1742-8130

Psychostimulants, Protein phosphorylation and Gene expression: a growing role of L-type calcium channels

Anjali M. Rajadhyaksha ¹ & Barry E. Kosofsky ²

Introduction

The psychostimulants, amphetamine and cocaine, exert their persistent addictive effects by activating neuronal second messenger pathways in the brain’s reward pathway (Berke and Hyman, 2000; Hyman and Malenka, 2001; Nestler, 2001a). The meso-accumbens and meso-striatal pathways that project form the ventral tegmental area (VTA), to the nucleus accumbens (NAc) and the dorsal striatum (caudate putamen), respectively, serve as the primary pathways targeted by psychostimulants (Pierce and Kalivas, 1997b; White and Kalivas, 1998; Everitt and Wolf, 2002; Gerdeman et al., 2003). The VTA serves as the primary nucleus at which amphetamine and cocaine activate neurotransmitter pathways that initiate molecular mechanisms (Bonci et al., 2003; Vezina, 2004) whereas the NAc and dorsal striatum represent sites at which molecular adaptations are consolidated following abstinence from drug exposure (Pierce and Kalivas, 1997b; Berke and Hyman, 2000; Hyman and Malenka, 2001). It is these adaptations that underlie life-long alteration in behavior both in human addicts and animal models of addiction (Hyman and Malenka, 2001; Robinson and Berridge, 2003). Psychostimulant-induced activation of second messenger pathways at the neuronal membrane leads to changes in protein phosphorylation and downstream gene expression. Over the last several years calcium neurotransmission via glutamate receptors has been the focus of the neurobiological basis of amphetamine and cocaine’s actions (Wolf, 1998, 2002). However, there is a growing body of literature that supports a role for voltage-gated L-type Ca²⁺ channels (LTCCs), a key mediator of neuronal plasticity (Deisseroth et al., 2003; Groth et al., 2003), in aspects of psychostimulant-dependent molecular and behavioral changes (Karler et al., 1991; Pierce and Kalivas, 1997a; Licata et al., 2000; Licata et al., 2001; Licata et al., 2003; Pliakas and Carlezon, 2001; Licata and Pierce, 2003; Rajadhyaksha et al., 2004).

LTCCs are voltage-gated Ca²⁺ channels that form heteromeric complexes on the neuronal membrane and are composed of a voltage-sensitive Ca²⁺ pore forming Cav or α1 subunit and auxiliary β, α2δ and γ subunits (Fig.1, Walker and De Waard, 1998). Two LTCC subunits have been found in the brain, the Cav1.2 (α1C) and Cav1.3 (α1D) subunit (Ertel et al., 2000). Activation of LTCCs results in influx of intracellular Ca²⁺ and activates either the Ca²⁺/calmodulin (CaM)-dependent kinase (CaMK) or Ca²⁺/CaM-dependent phosphatase pathways (Fig.2, Rajadhyaksha et al., 1999; Chang and Berg, 2001; Wu et al., 2001a, b; Deisseroth et al., 2003; Groth et al., 2003; Snyder et al., 2003). The two primary kinase pathways activated by LTCCs are the Ca²⁺/CaM kinase (CaMK) and the MAP (ERK1/2) kinase pathways, and the primary phosphatase pathway is the calcineurin (PP2B) pathway. In the VTA, NAc and dorsal striatum both these pathways activate intraneuronal mediators involved in psychostimulant actions that leads to the downstream activation of the transcription factor CREB (cyclic AMP response element-binding protein) and CREB-mediated gene expression, which are critical mediators of psychostimulant-induced neuronal plasticity (Berke and Hyman, 2000; Nestler, 2001a, 2001b, 2002).

Contribution of Cav1.2 containing L-type Ca²⁺ channels to psychostimulant-induced plasticity in the VTA

Activation of gene expression and new protein synthesis in the VTA plays a pivotal role in long-lasting psychostimulant-induced behaviors (Sorg and Ulibarri, 1995). The dopamine-releasing neuron serves as the primary cell type in the VTA where molecular mechanisms are initiated (Bonci et al., 2003; Vezina, 2004). It is well known that dopamine, glutamate and their respective signaling pathways are critical for psychostimulant-induced signaling in the VTA (Wolf, 1998; Vezina and Queen, 2000; Ungless et al., 2001; Carlezon and Nestler, 2002; Suto et al., 2002; Wolf, 2002; Saal et al., 2003). In addition there is increasing evidence for a postsynaptic contribution of LTCCs downstream to those of dopamine and glutamate signaling within the adaptations that occur from acute to chronic psychostimulant exposure (Pierce et al., 1998; Rajadhyaksha et al., 2004). An interesting finding from behavioral studies is the observation that LTCCs are not required for the acute behavioral response to psychostimulants, but are necessary for the neuronal adaptations that underlie repeated psychostimulant exposure (Pierce et al., 1998). This is consistent at the molecular level where acute amphetamine administration activates the Ca²⁺/CaM second messenger pathway by increasing CaM mRNA and protein expression (Michelhaugh and Gnegy, 2000), and the phosphorylation of ERK1/2 (Rajadhyaksha et al., 2004). This acute effect does not involve LTCCs (Rajadhyaksha et al., 2004) and is predominantly mediated by activation of the NMDA receptor subtype of the glutamate receptor (Sweatt, 2001; Thomas and Huganir, 2004) and the neurotrophic factor, neurotrophin-3 (Pierce et al., 1999, Fig.3a). This is also consistent with the finding that Cav1.2 mRNA and protein, an activator of the ERK1/2 pathway (Dolmetsch et al., 2001), is expressed at very low levels in VTA dopamine neurons (Fig.3b, Rajadhyaksha et al., 2004) and undergoes an increase in its mRNA and protein level following repeated exposure to amphetamine (Rajadhyaksha et al., 2004). In addition repeated amphetamine has been found to activate the Ca²⁺/CaM-dependent phosphatase pathway with increases in levels of the phosphatases PP2B and MAP kinase phosphatase-1 (Rajadhyaksha et al., 2004). Taken together, these findings suggest that activation of Cav1.2-mediated pathway and the PP2B pathway in the VTA represent one of the adaptations that contribute to psychostimulant-induced neuronal plasticity and altered behavior.

Figure 3. VTA neuron responses to amphetamine exposure

L-type Ca²⁺ channels in psychostimulant-activated molecular pathways in the nucleus accumbens and dorsal striatum

In the NAc and dorsal striatum, the predominant neurotransmitter tracts activated in response to amphetamine and cocaine exposure are the dopamine and glutamate pathways. Dopamine via D1 and D2 receptors regulates the cyclic AMP (cAMP)/protein kinase A (PKA) cascade, and glutamate via the AMPA and NMDA receptors regulates Ca²⁺/CaM signaling (White and Kalivas, 1998; Berke and Hyman, 2000; Hyman and Malenka, 2001; Kelley, 2004). LTCCs have been found to influence both these second messenger pathways. Studies in striatal slices and cultures have revealed that LTCCs and Cav1.3 mediate components of D1 (Surmeier et al., 1995; Liu and Graybiel, 1996; Cepeda et al., 1998; Olson et al., 2005), D2 (Hernandez-Lopez et al., 2000; Olson et al., 2005) and glutamate (Cepeda et al., 1998; Rajadhyaksha et al., 1999; Cooper and White, 2000) signaling.

The most extensively studied pathway in the dorsal striatum, and to a lesser extent in the NAc, is the dopamine and adenosine 3’, 5’-monophosphate-regulated phosphoprotein (DARPP-32) pathway (Greengard, 2001). DARPP-32 is an important mediator of psychostimulant-induced molecular and behavioral changes (Fienberg et al., 1998; Snyder et al., 2000; Zachariou et al., 2002; Valjent et al., 2005). DARPP-32 is a phosphoprotein regulated by PKA and PP2B that integrates cAMP signals activated by D1 receptors and the Ca²⁺/CaM pathway activated by NMDA receptors and LTCCs (Fig.4a, Liu and Graybiel, 1996; Greengard et al., 1999). Dependent upon its state of phosphorylation, DARPP-32 regulates the phosphorylation of CREB and CREB-mediated gene expression, a critical mediator of psychostimulant-induced plasticity in the NAc and dorsal striatum (Carlezon et al., 1998; Nestler, 2002; McClung and Nestler, 2003; Nestler, 2004). Following acute psychostimulant exposure and dopamine D1 agonist treatment, DARPP-32 is phosphorylated at Thr 34, a PKA specific site (Hemmings et al., 1984b). Once phosphorylated, DARPP-32 becomes a potent inhibitor of protein phosphatase 1 (PP1), a phosphatase that dephosphorylates CREB (Hemmings et al., 1984a). Inhibition of PP1 and activation of PKA results in an increase in CREB phosphorylation that activates downstream CREB-mediated gene expression (Rajadhyaksha et al., 1998; Rajadhyaksha et al., 1999). LTCCs have been found to contribute to the DARPP-32/CREB second messenger pathway via activation of either the Ca²⁺/CaM-dependent kinase or Ca²⁺/CaM-dependent phosphatase pathways. Following acute psychostimulant exposure via D1 and NMDA receptors, LTCCs increase levels of intracellular Ca²⁺ and thus activate Ca²⁺/CaM kinases, resulting in CREB phosphorylation and activation of gene expression (Liu and Graybiel, 1996, 1998; Rajadhyaksha et al., 1999). LTCCs have also been found to activate the calcineurin pathway (Liu and Graybiel, 1996; Snyder et al., 2003). While the precise pathway activated by LTCCs in the dorsal striatum and NAc in response to repeated psychostimulant exposure is not known, it can be speculated that high intracellular Ca²⁺ elevations that promote kinase activation would dominate following acute psychostimulant exposure, whereas conditions that lead to modest or low Ca²⁺ increases would shift the equilibrium towards activation of phosphatases (Malenka, 1994; Nicoll and Malenka, 1995; Bear and Abraham, 1996, Fig.4b). A clue to the potential contribution of LTCCs in activating the Ca²⁺/CaM-dependent phosphatase pathway in response to repeated psychostimulants comes from the observation that following recurrent cocaine exposure NAc neurons exhibit long-term depression (Thomas et al., 2001), a phenomenon associated with decreased intracellular Ca²⁺ activity and increased phosphatase activity (Winder and Sweatt, 2001), as well as decreased basal levels of intracellular Ca²⁺ and increased PP2B signaling (Zhang et al., 2002). This is further supported by a recent finding that DARPP-32, a downstream target of PP2B is dephosphorylated in the NAc and dorsal striatum following recurrent cocaine exposure (Scheggi et al., 2004).

Figure 4. Acute (A) and Prolonged (B) responses of NAc and striatal neurons to amphetamine

While the precise role of Cav1.2 and Cav1.3 subtypes in psychostimulant-induced molecular signaling is not yet known, both these subtypes have been found to phosphorylate CREB and activate CREB-mediated gene expression (Dolmetsch et al., 2001; Sinnegger-Brauns et al., 2004; Zhang et al., 2005). The functional and regional specificity of the intracellular pathways they activate is conferred by their presence in multi-protein signaling complexes which consist of an anchoring or scaffolding protein that secures a kinase and a phosphatase in close proximity to the channel allowing regulation of channel activity via phosphorylation (Fig.6). In the dorsal striatum, LTCC phosphorylation is regulated by D1 and D2 receptors (Surmeier et al., 1995; Rakhilin et al., 2004). D1 receptors via activation of PKA phosphorylate LTCCs at a PKA specific site thereby increasing channel activity (Surmeier et al., 1995, Fig.5). On the other hand, D2 receptors via the phospholipase (PLC)/Ca²⁺/PP2B pathway dephosphorylates LTCCs (Hernandez-Lopez et al., 2000; Rakhilin et al., 2004, Fig.5).

Cav1.2 and Cav1.3 have been found to associate with different intracellular targeting molecules, suggesting differential regulation by phosphorylation and contribution to neuronal signaling (Fig.6). Cav1.2 associates with the microtubule-associated protein MAP2B, a member of the A-kinase anchoring protein (AKAP) family (Davare et al., 1999), and with the catalytic subunit of PKA (PKAc) and protein phosphatase 2A (PP2A, Davare et al., 1999; Davare et al., 2000). In addition Cav1.2 contains the PDZ interaction sequence, Val-Ser-Asn-Leu (VSNL) at its C-terminus that has been identified as being critical for Cav1.2-mediated CREB phosphorylation and CREB-mediated gene expression (Weick et al., 2003). The proteins that associate with Cav1.3 have not yet been identified, although Cav1.3 also contains a PKA-dependent phosphorylation site with the potential of being regulated by amphetamine and cocaine. Similar to Cav1.2, Cav1.3 contains a PDZ interaction sequence Ile-Thr-Thr-Leu (ITTL) and Src homology3 (SH3) domain, unique to itself, that enables interactions with the synaptic scaffolding protein Shank (SH3 domain and ankyrin repeat containing protein, Kennedy, 1998; Sheng and Kim, 2000). Shank in turn can binds to the adaptor protein, Homer that regulates intracellular Ca²⁺ stores (Xiao et al., 2000; Olson et al., 2005). In dorsal striatal cultures, dopamine D2 receptors have been found to modulate Cav1.3 signaling via a mechanism dependent on the Cav1.3/Shank interaction (Olson et al., 2005). In addition Homer in the NAc has recently been identified as a factor involved in cocaine-induced behaviors (Szumlinski et al., 2004). Furthermore, a recent study using transgenic mice that allows specific manipulation of the Cav1.3 subtype has revealed region-specific roles for Cav1.2 and Cav1.3 in activating the CREB-regulated gene, fos (Sinnegger-Brauns et al., 2004). In the dorsal striatum, Cav1.2 activates Fos protein expression whereas in the NAc, increased Fos expression is mediated by Cav1.3.

In summary, there is strong and growing evidence for a pivotal role of L-type Ca²⁺ channels, and specifically its subtypes Cav1.2 and Cav1.3 and their associated Ca²⁺ activated pathways in mediating aspects of the addictive properties of the psychostimulants amphetamine and cocaine.

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