Ca2+ Channels As Integrators of G Protein-Mediated Signaling in Neurons

Abstract

The observations from Dunlap and Fischbach that transmittermediated shortening of the duration of action potentials could be caused by a decrease in calcium conductance led to numerous studies of the mechanisms of modulation of voltagedependent calcium channels. Calcium channels are well known targets for inhibition by receptor-G protein pathways, and multiple forms of inhibition have been described. Inhibition of Ca 2ϩ channels can be mediated by G protein ␤␥-subunits or by kinases, such as protein kinase C and tyrosine kinases. In the last few years, it has been shown that integration of G protein signaling can take place at the level of the calcium channel by regulation of the interaction of the channel pore-forming subunit with different cellular proteins.Communication between neurons and their targets depends upon the precise timing of electrical and chemical signals. In the nervous system, short, local signals are necessary to convey appropriate timing information. Defects in such timing events produce problematic errors in the final physiological response. Voltage-dependent calcium channels are the primary triggers for electrically evoked release of chemical transmitters; therefore, understanding the molecular components and events underlying their regulation is central to the development of a mechanistic picture of key events in neuronal signaling. Inhibition of Ca 2ϩ channels can be voltage-dependent and is mediated by direct interaction of G protein ␤␥-subunits with the pore-forming ␣ 1 -subunit of the channel (Hille, 1994;Ikeda and Dunlap, 1999). In addition, phosphorylation by kinases such as protein kinase C (Rane and Dunlap, 1986) and tyrosine kinases (Diversé-Pierluissi et al., 1997) has been shown to inhibit Ca 2ϩ channels. Classification and Structure of High-VoltageActivated Calcium ChannelsHigh voltage-activated calcium channels are classified into Ca v 1.1-3 and Ca v 2.1-3 types based on the gene encoding the pore subunit and their electrophysiological and pharmacological properties. Ca v 1-type channels are ubiquitous (Table 1). They play an important role in excitation-contraction in cardiac and skeletal muscle (Catterall, 2000). Ca v 2.1 and Ca v 2.2 channels are involved in neurotransmission and can coexist in the same nerve terminals (Dunlap et al., 1995). Until recently, the Ca v 2.3 channel was less characterized because of its lack of sensitivity to any known pharmacological blocker. The use of SNX482 as a blocker for this type of channel should facilitate the studies of the function and regulation of Ca v 2.3 channels (Bourinet et al., 2001).Voltage-dependent calcium channels are multimeric proteins composed of ␣ 1 -, ␤-, ␣ 2 ␦-, and ␥-subunits (Fig. 1). The ␣ 1 -subunit is the pore-forming subunit and accounts for the voltage-dependence of the channel. Channel blockers and naturally occurring toxins exert their actions by binding to this subunit. So far, four ␤-subunits, four ␦-subunits (Qin et al., 2002), and eight ␥-subunits (Tomita et al., 2003)

Caveolin-1 alters Ca2+ signal duration through specific interaction with the Gαq family of G proteins

“…This can be important for signaling diversity and receptor cross-talk through Gβγ exchange (Quitterer and Lohse, 1999). Gβγ subunits are regulators of certain Ca 2+ channels and modulation of Ca 2+ can occur via activation of PKC through activated Gα q (Dascal, 2001;Strock and Diversé-Pierluissi, 2004;Wickman and Clapham, 1995). Here, the observed physical separation of Gα q and Gβγ, and Ca 2+ mobilization, are very specific to Cav1 expression, and the control cells (FRTcav -) showed no such effect under identical experimental conditions.…”

Different kinases regulate activation of voltage-dependent calcium channels by depolarization in GH3 cells

“…The L-type Ca 2ϩ channel is the primary voltage-dependent Ca 2ϩ -influx pathway in many excitable and other secretory cells. Its pore-forming ␣ 1 -subunit contains NH 2 -and COOH-terminal cytosolic domains, which are potential targets for protein phosphorylation (44). Therefore, the activity of L-type Ca 2ϩ channels can be regulated by different types of kinases, such as PKA and PKC.…”

“…The pore-forming ␣ 1 -subunit accounts for the voltage dependence of the channel. These channels are classified on the basis of the gene encoding the pore subunit and their electrophysiological and pharmacological properties (44). The L-type Ca 2ϩ channel is the primary voltage-dependent Ca 2ϩ -influx pathway in many excitable and other secretory cells.…”

G(o) activation is required for both appetitive and aversive memory acquisition in Drosophila

“…Presynaptic voltage-gated Ca 2+ channels represent a major effector for G(o) (Strock and Diverse-Pierluissi 2004). G-protein bg-subunits inhibit N-type (Ca v 2.2) and P/Qtype (Ca v 2.1) presynaptic Ca 2+ channels involved in neurotransmitter release (Herlitze et al 1996;Ikeda 1996), causing a positive shift in their voltage dependence of activation.…”