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

Abstract

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 at least partially by the tissue-specific expression of alternatively spliced IS6 segments of the alpha 1C gene.

Developmental Activation of Calmodulin-Dependent Facilitation of Cerebellar P-Type Ca2+Current

“…Twenty to 30 bacterial colonies (derived from a single neuron) were then PCR amplified with splice-specific primers (bottom right, 220 bp), enabling determination of the ratio of EFa to EFb transcripts in individual neurons (Fig. 4 E) (Welling et al, 1997;Regan et al, 2000;Splawski et al, 2004;Fan et al, 2005). Whereas EFa and EFb were equivalent at 5 d, EFa predominated by 12 d. Although the relative increase of EFa transcript was less pronounced than the age-dependent elevation of CDF (Fig.…”

Molecular Pharmacology of T-type Ca2+ Channels

“…Second generation blockers such as nimodipine display greater selectivity for vascular beds (11). Two mechanisms that contribute to this selectivity are: 1) state dependent block, where drugs preferentially block partially inactivated channels, and 2) tissue specific expression of Cav1.2 splice variants that have distinct sensitivity to the drugs (12).…”

Human vascular to cardiac tissue selectivity of L‐ and T‐type calcium channel antagonists

“…Welling et al (1997) showed that spliced variants of the IS6 segment of the a IC gene (a IC-a and a IC-b ) were speci®cally located in rat ventricular myocytes (a IC-a ) and in rat aorta (a IC-b ) and that nisoldipine showed greater sensitivity against the a IC-b vascular L-type channel than against the a IC-a cardiac channel. Thus the basis for vascular to cardiac selectivity of VOCC antagonists may involve the density and location of the broad type of VOCC (T and L), the possibility of alternative spliced segments of the critical voltage-gated pore protein, if located to speci®c tissues, and the resting membrane potential.…”