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calcium channel, voltage-dependent, gamma subunit 3
The protein encoded by CACNG3 is a type I transmembrane AMPA receptor regulatory protein (TARP). 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 childhood absence epilepsy.
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 ). Interestingly, these clusters also mirror to some extent the tissue distribution of the subunits and their likely cellular functions. (Chen )
Cacng3 : calcium channel, voltage-dependent, gamma subunit 3
c2, c3 (=cacng3, the third gamma unit), c4, and c8 contain several common regulatory sites in both the extracellular and intracellular domains. 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 , Choi ). This combination determines the synaptic targeting of TARPs and AMPA receptors. In addition, the nPIST- binding motifs in the center portion of the C-terminal tail of TARPs regulates membrane-trafficking and synaptic targeting of the TARPs (Cuadra ). A series of nine serine residues in the N-terminal portion of nPIST-binding motif are regulated by kinases (CAMKII, PKC) and phosphatases (PP2B and PP1). A tyrosine sulfation site also exists in the first extracellular loop of the TARPs. Tyrosine sulfation occurs when proteins travel through the Golgi lumen. This modification strengthens protein–protein interactions and is usually observed in proteins involved in intercellular interactions and communication. (Chen )
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 )