Alternatively spliced IS6 segments of the alpha(1C) gene determine the tissue-specific dihydropyridine sensitivity of cardiac and vascular smooth muscle L-type Ca2+ channels

Dihydropyridines (DHPs) block the vascular smooth muscle L-type Ca2+ channel at lower concentrations than the cardiac Ca2+ channel, although their alpha(1) subunit, which binds the DHPs, is derived from the same gene. This alpha(1C) gene gives rise to several splice variants, among which the alpha(1C-b) variant is affected by lower concentrations of nisoldipine than the alpha(1C-a) variant. Functional expression of chimeras of alpha(1C-a) and alpha(1C-b) subunits demonstrated that the transmembrane segment IS6 is responsible for the different dihydropyridine sensitivity. Northern blot analysis showed that transcripts coding for the IS6 segment of the alpha(1C-a) subunit were expressed in heart but not in aorta, whereas the IS6 segment of the alpha(1C-b) subunit was expressed predominantly in vascular smooth muscle. In situ hybridization of rat heart sections confirmed this expression pattern of IS6 alpha(1C-a) and IS6 alpha(1C-b) in ventricular and smooth muscle myocytes, respectively. These results suggest that the different dihydropyridine sensitivities of cardiac and vascular L-type Ca2+ channels are caused al least partially by the tissue-specific expression of alternatively spliced IS6 segments of the alpha(1C) gene.