L-type Ca2+ channel is a member of the family of voltage-dependent ion channels. The cDNA for the human fibroblast Ca2+ channel (CACNL1A1) was previously characterized. Sequence analysis demonstrated regional heterogeneity of the channel transcripts due to the alternative splicing in four defined positions. To understand better the genetic mechanisms involved in regulation of Ca2+ channel expression, the genomic organization of the human L-type Ca2+ channel gene was examined. The CACNL1A1 gene spans an estimated 150 kb of the human genome and is composed of 44 invariant and 6 alternative exons. In the region encoding transmembrane segment IIS6, there is a splice site structurally favorable for generation of transcripts with interrupted open reading frames. Comparison of the human fibroblast versus hippocampus transcripts for a cytoplasmic tail region indicates that splicing of the Ca2+ channel primary transcript may occur in a tissue-specific manner, utilizing non-coding nucleotide sequences for new exons. Evidence is presented that isoforms of the L-type Ca2+ channel gene exist in the human genome.