A novel long N-terminal isoform of human L-type Ca2+ channel is up-regulated by protein kinase C

Human L-type voltage-dependent CA(2+) channels (Alpha(1C), or CA(v)1.2) are up-regulated by protein kinase C (PKC) in native tissues, but in heterologous systems this modulation is absent. In rat and rabbit, Alpha(1C) has two N-terminal (NT) isoforms, long and short, with variable initial segments of 46 and 16 Amino acids, respectively. The initial 46 Amino acids of the long-NT Alpha(1C) are crucial for PKC regulation. However, only a short-NT human Alpha(1C) is known. We assumed that a long-NT isoform of human Alpha(1C) may exist. By homology screening of human genomic DNA, we identified a stretch (termed exon 1a) highly homologous to rabbit long-NT, separated from the next known exon of Alpha(1C) (exon 1b, which encodes the alternative, short-NT) by an approximately 80 kb-long intron. The predicted 46-amino acid protein sequence is highly homologous to rabbit long-NT. Reverse Transcriptase PCR showed the presence of exon 1a transcript in human cardiac RNA. Expression of human long-NT Alpha(1C) in Xenopus oocytes produced CA(2+) channel enhanced by a PKC Activator, whereas the short-NT Alpha(1C) was inhibited. The long-NT isoform may be the CA(2+) channel enhanced by PKC-activating transmitters in human tissues.