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calcium channel, voltage-dependent, gamma subunit 2
The second member of the calcium channel gamma subunit family, gamma2 (=CACNG2), was identified from genetic analysis of the stargazer mouse, an animal that displays a characteristic phenotype that includes head tossing and epileptic episodes (Noebels ).
CACNG2 (also known as FLJ41437; MGC138502; MGC138504) encodes a type I transmembrane AMPA receptor regulatory protein (TARP), also known as a gamma2 subunit. TARPs regulate both trafficking and channel gating of the AMPA receptors. This gene is part of a functionally diverse eight-member protein subfamily of the PMP-22/EMP/MP20 family. This gene is a susceptibility locus for schizophrenia.
Phylogenetic analysis suggests that all c subunits evolved from a single ancestral gene through tandem repeat and chromosome duplication (Burgess , Chu ). Based on sequence homology and chromosomal linkage the c subunits can be divided into three clusters: (c1, c6), (c5, c7), and (c2, c3, c4, c8) (Burgess , Chu ).
Cacng2 : calcium channel, voltage-dependent, gamma subunit 2
In addition to the critical PDZ-binding motif, the C-terminal regions of the four gamma (c) subunits known as the TARPs (c2, c3, c4, c8) also contain regulatory sites that control AMPA receptor targeting. For instance, the second threonine in the PDZ-binding motif (TTPV) of c2 (=cacng2) is a consensus site for phosphorylation by PKA, PKC, PKG, and CaMKII suggesting that phosphorylation may regulate the interaction between c2 and the AMPA receptor. Indeed, two groups have independently found that phosphorylation by PKA interfered with the binding between c2 and PSD-95 (Chetkovich , Choi ). Consequently, reduced synaptic targeting of c2 prevents its interaction with the AMPA receptor, resulting in weakened synaptic efficiency (Choi ).
The eight calcium channel c subunits share a predicted structure that includes four transmembrane domains with intracellular N- and C- termini (Fig. 1 in Chen ). They are members of a large protein superfamily (pfam00822, a subset of the tetraspanin supergroup) that also includes claudins, proteins that are important components of tight junctions in epithelia. The c subunits share with the claudins a conserved GLW motif of unknown significance in the first extracellular loop. (Chen )
The four c subunits identified as regulators of AMPA receptor function (c2, c3, c4, and c8; the TARPs) are widely expressed in the brain and share highly conserved sequences that are quite distinct from c1 and c6 (Arikkath , Black ). Notably, the cytoplasmic C-terminal regions of the TARPs contain a number of regulatory sites including a PDZ-binding motif. This PDZ-binding motif (TTPV) is critical for targeting AMPA receptors to the synapse. (Chen )
c2, c3, and c4 are reported to hyperpolarize the voltage-dependence of inactivation of Cav2.1 (HVA) current by 3–7 mV (Klugbauer , Letts , Rousset ). However, the direction of this shift is apparently altered when a b subunit is co-expressed (Rousset ). Two studies have reported small (3–5 mV) shifts in the voltage- dependence of activation by c2 but in different directions (Klugbauer , Rousset ). The only reported effect of c2, c3, and c4 on Cav3.3 (LVA) current is that c2 slows the deactivation rate of Cav3.3 channel (Green ). Unlike the results with c1 and c6, significant decreases in current amplitude were not rou- tinely found with any of the TARPs, although modulation of Cav2 current amplitude has been reported (Kang ). Currently, there is no evidence supporting an effect of these subunits on calcium currents in native cells. Specifically, there are no observable changes in calcium currents recorded from cerebellar granule neurons in the stargazer mouse in which the c2 gene is mutated (Chen ).