The C-terminus of P/Q type voltage gated calcium channel Alpha1A subunit (Cav2.1) modulates the transcription of the other neuronal genes.

The CACNA1A gene on chromosome 19p13 encodes the alpha1A subunit of P/Q type voltage-gated Ca2+ channels (Cav2.1) expressed mainly in the cerebellum (in Purkinje and granule cells) and at the neuromuscular junction. Mutations in this gene are responsible for three rare autosomal dominant neurological disorders: Episodic Ataxia 2 (EA2), Familial Hemiplegic Migraine 1 (FHM1) and Spinocerebellar Ataxia 6 (SCA6) due to the expansion of a CAG repeat at the 3'end of the gene. The Cav2.1 alpha1A subunit is a four domain transmembrane protein of about 280KDa with cytoplasmic N- and C-terminal tails. The cytoplasmic C-terminus plays regulatory roles in the gating and trafficking of many ion channels. The C-terminus of the Cav2.1 alpha1A subunit, which represent the 25% of the entire protein (about 700 aminoacids) and contains the CAG repeat expanded in SCA6, plays a regulatory role in gating and trafficking and contains residues involved in channel inactivation and modulation induced by intracellular signalling proteins. Recently, the C-terminal tail was shown to be cleaved in vivo and conveyed into the nucleus, suggesting its involvement in regulating some transcriptional processes. In order to elucidate the role of the Cav2.1 C-terminal tail as possible transcription factor, gene expression arrays were carried out in HEK293 cell line wild type and over-expressing Cav2.1 C-terminal tail. Total RNA, extracted from these cells, was analyzed using Agilent 44K whole human genome oligo microarray system. Gene expression in HEK293 cells wild type and over-expressing Cav2.1 C-terminal tail was compared and for genes resulted up or down-regulated more than 5 folds, the expression profile was checked by using standard qRT-PCR analysis. These results, for the first time, provide evidence that Cav2.1 C-terminus, beside modulating channel activity, regulates the expression of genes important for the neuronal excitability such as gap junctions, ion channels, signalling proteins.