Voltage-dependent calcium channel, gamma-2 subunit (VDCC_g2su)
Type: Family

Ca2+ ions are unique in that they not only carry charge but they are also the most widely used of diffusible second messengers. Voltage-dependent Ca2+ channels (VDCC) are a family of molecules that allow cells to couple electrical activity to intracellular Ca2+ signalling. The opening and closing of these channels by depolarizing stimuli, such as action potentials, allows Ca2+ ions to enter neurons down a steep electrochemical gradient, producing transient intracellular Ca2+ signals. Many of the processes that occur in neurons, including transmitter release, gene transcription and metabolism are controlled by Ca2+ influx occurring simultaneously at different cellular locales. The pore is formed by the alpha-1 subunit which incorporates the conduction pore, the voltage sensor and gating apparatus, and the known sites of channel regulation by second messengers, drugs, and toxins . The activity of this pore is modulated by four tightly-coupled subunits: an intracellular beta subunit; a transmembrane gamma subunit; and a disulphide-linked complex of alpha-2 and delta subunits, which are proteolytically cleaved from the same gene product. Properties of the protein including gating voltage-dependence, G protein modulation and kinase susceptibility can be influenced by these subunits.

Voltage-gated calcium channels are classified as T, L, N, P, Q and R, and are distinguished by their sensitivity to pharmacological blocks, single-channel conductance kinetics, and voltage-dependence. On the basis of their voltage activation properties, the voltage-gated calcium classes can be further divided into two broad groups: the low (T-type) and high (L, N, P, Q and R-type) threshold-activated channels.

The voltage-dependent calcium channel gamma (VDCCG) subunit family consists of at least 8 members, which share a number of common structural features . Each member is predicted to possess 4 transmembrane domains, with intracellular N-and C-termini. The first extracellular loop contains a highly conserved N-glycosylation site and a pair of conserved cysteine residues. The C-terminal 7 residues of VDCCG-2, -3, -4 and -8 are also conserved and contain a consensus site for phosphorylation by cAMP and cGMP-dependent protein kinases, and a target site for binding by PDZ domain proteins .

The VDCCG-2 subunit (also known as stargazin) was isolated by identifying the locus of the genetic disruption in the epileptic mouse mutant line known as stargazer . VDCCG-2 subunits are brain specific and enriched in synaptic plasma membranes. In vitro studies using recombinant P/Q-type calcium channels show that VDCCG-2 subunit expression increases steady-state channel inactivation, leading to the suggestion that, in stargazer mutants, inappropriate calcium entry may contribute to the seizure phenotype.

VDCCG-2 subunits are also implicated in cellular trafficking. They interact with ionotropic glutamate AMPA receptor subunits, a process that has been shown to be essential in delivering functional AMPA receptors to the surface membranes of cerebellar granule cells . In addition, VDCCG-2 subunits are capable of associating with PDZ proteins, such as PSD-95, through their C-terminal PDZ binding domains. This interaction is required to target AMPA receptors to cerebellar synapses.