Cavγ4

The protein encoded by CACNG4 (also known as MGC11138; MGC24983) is a type I transmembrane AMPA receptor regulatory protein (TARP), also known as gamma4 (c4) 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 and is located in a cluster with two family members, a type II TARP and another calcium channel gamma subunit.

http://www.ncbi.nlm.nih.gov/gene/27092

Phylogenetic analysis suggests that all c subunits evolved from a single ancestral gene through tandem repeat and chromosome duplication (Burgesse [1312], Chu [1311]). 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) (Burgesse [1312], Chu [1311]). See also the phylogenetic tree, fig.2 in Black [478].

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 [1324], Black [478]).

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 [1310]). 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 [1310]

The cytoplasmic C-terminal regions of the TARPs (to which cacng4 = gamma4 = c4 belongs) 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 [1310]

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 [1324], Black [478]).

γ 4 mRNA was highly expressed in caudate putamen, olfactory bulb, habenulae and less so in cerebellum and thalamus. γ 2 and γ 4 expression in cerebellum came predominantly from Purkinje cells. (Black [478])

γ 4 was expressed broadly in brain with very strong expression in fetal brain and some increased expression in caudate nucleus, putamen, and thalamus. There was substantial expression in prostate and lung and less expression in testes, stomach, pancreas, small intestine, placenta, and uterus. Because γ 4 was highly expressed in fetal brain, it is hypothesized to have a potential role during development. This hypothesis is supported by Kious et al. (2002) [1334] who found γ 4 expression in the chick cranial neural plate and in the cranial and dorsal root ganglia. Timing of expression correlates precisely with the onset of neuronal differentiation. γ 4 expression is also observed in the myotome and a subpopulation of differentiating myoblasts in the limb bud. In the distal cranial ganglia, γ 4 expression was detected in cells destined to become neurons and neural crest cells. The authors hypothesize that γ 4’s subtle effects on VGCC calcium transients effects neuronal differentiation. (Black [478])

The most distinct features of the TARPs are the terminal PDZ-binding motifs overlapped with PKA phosphorylation sites. The terminal TTPV motif is known to interact with PSD-95 in the postsynaptic density and the binding is regulated by the PKA motif immediately preceding the PDZ-binding motif (Chetkovich [1325], Choi [1326]). In addition to the critical PDZ-binding motif, the C-terminal regions of the four c subunits known as the TARPs (c2, c3, c4, c8) also contain regulatory sites that control AMPA receptor targeting. (Chen [1310])