Alternatively Spliced IS6 Segments of the α 1C Gene Determine the Tissue-Specific Dihydropyridine Sensitivity of Cardiac and Vascular Smooth Muscle L-Type Ca 2+ Channels

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Abstract
Dihydropyridines (DHPs) block the vascular smooth muscle L-type Ca2+ channel at lower concentrations than the cardiac Ca2+ channel, although their α1 subunit, which binds the DHPs, is derived from the same gene. This α1C gene gives rise to several splice variants, among which the α1C-b variant is affected by lower concentrations of nisoldipine than the α1C-a variant. Functional expression of chimeras of α1C-a and α1C-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 α1C-a subunit were expressed in heart but not in aorta, whereas the IS6 segment of the α1C-b subunit was expressed predominantly in vascular smooth muscle. In situ hybridization of rat heart sections confirmed this expression pattern of IS6 α1C-a and IS6 α1C-b in ventricular and smooth muscle myocytes, respectively. These results suggest that the different dihydropyridine sensitivities...