The impact of splice isoforms on voltage-gated calcium channel alpha1 subunits

Abstract

Semi-conserved exon boundaries in members of the CACNA1 gene family result in recurring pre-mRNA splicing patterns. The resulting variations in the encoded pore-forming subunit of the voltage-gated calcium channel affect functionally significant regions, such as the vicinity of the voltage-sensing S4 segments or the intracellular loops that are important for protein interaction. In addition to generating functional diversity, RNA splicing regulates the quantitative expression of other splice isoforms of the same gene by producing transcripts with premature stop codons which encode two-domain or three-domain channels. An overview of some of the known splice isoforms of the alpha(1) calcium channel subunits and their significance is given.

Figure 1. Calcium channel nomenclature (modified according to Ertel et al. 2000)

Figure 2. Scheme of the voltage-gated calcium channel α₁ subunit

The α₁ subunit of voltage gated calcium channels consists of four domains (repeats) of six transmembrane segments connected by intracellular loops. A, conservation of the gene structure at the protein level as determined by protein alignments encoded by all exons of all 10 members of the CACNA1 family. Each protein region encoded by an exon is delineated by bars. White, black and grey bars indicate degree of conservation as noted in the figure. The following human reference sequences were used at NCBI: Ca_v2.1: NP_075461; Ca_v2.2: NP_000709; Ca_v1.2: NP_000710; Ca_v1.3: NP_000711; Ca_v2.3: NP_000712; Ca_v1.4: NP_005174; Ca_v3.1: NP_061496; Ca_v3.2: NP_066921; Ca_v3.3: NP_066919; and Ca_v1.1: NP_000060. B, regions of the protein that are affected by alternative splicing. Note that the changes now reflect the protein level only (i.e. deletions leading to frame shifts and early truncations are marked as truncation only). The diversity of the primary protein sequence due to insertions, deletions, truncations and alternative sequences is marked by the various symbols.