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.