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calcium channel, voltage-dependent, gamma subunit 6
Voltage-dependent calcium channels are composed of five subunits. The protein encoded by the gene CACNG6 represents one of these subunits, gamma, and is one of two known gamma subunit proteins. This particular gamma subunit is an integral membrane protein that is thought to stabilize the calcium channel in an inactive (closed) state. 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 that function as transmembrane AMPA receptor regulatory proteins (TARPs). Alternative splicing results in multiple transcript variants. Variants in this gene have been associated with aspirin-intolerant asthma.
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 ).
Cacng6 : calcium channel, voltage-dependent, gamma subunit 6
All cs contain N-linked glycosylation sites in the first extracellular loop. However, only c1 and c6 have sites both before and after the signature GLW motif. Since the interaction between c1 and Cav1.1 is mapped to the first half of c1, the N43 and N80 residues of c1 might be good candidates for mutation analysis. Similarly these glycosylation sites may also be involved in the interaction between c6 and Cav3.1. c6 contains a unique palmitoylation site in the cytoplasmic end of the second transmembrane domain. Since palmitoylation increases membrane targeting of modified proteins (Chien , Van Itallie ) c6 may have a different intracellular distribution than that of c1. Alternatively, dynamic palmitoylation of c6 may provide a functional switch for the modulation of VDCCs. (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. The c1 and c6 subunits are distinguished from the other c subunits by their very short C-terminal cytoplasmic regions that lack functional motifs. (Chen )
The distribution of putative phosphorylation sites within c1 and c6 is not highly conserved. The intracellular N- termini of c1 contains a putative PKC site and that of c6 contains a putative PKA site in mouse and rat but not in human. A casein kinase II site appears in the C-terminal tail of c1 in all three species but does not exist in c6. We have also analyzed the phosphorylation sites in c1 and c6 using a neural networked-based prediction (Blom ) and reached a similar conclusion. In contrast to the numerous functional motifs in other c subunits, the phosphorylation sites on c1 and c6 are scarce and mostly not conserved. It would appear that the physiological functions of c1 and c6 are not extensively regulated by protein phosphorylation. The short length (19–20 aa) of the C-terminal tails on c1 and c6 also preclude the existence of more than a few sites as targets of intracellular signaling. (Chen )
c6 subunit is expressed in both skeletal and cardiac muscles, and to a lesser extent, in brain (Chu , Burgess , Fukaya ). Although an initial report failed to find c6 expression in human cardiac tissue (Chu ), microarray data (the Gene Expression Omnibus at http:// www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo) confirm the presence of c6 mRNA in human heart (Accession number: GDS651, GDS839) as well as human skeletal muscle (GDS264, GDS611). As was previously seen in rat (Burgess ), short isoforms of c6 lacking the second and third transmembrane domains are expressed in human tissue. The c6 subunit is the only member of the c subunit family that is expressed as separate isoforms. (Chen )