The action of calcium channel blockers on recombinant L-type calcium channel α₁-subunits

Abstract

1. CHO cells expressing the α_1C-a subunit (cardiac isoform) and the α_1C-b subunit (vascular isoform) of the voltage-dependent L-type Ca²⁺ channel were used to investigate whether tissue selectivity of Ca²⁺ channel blockers could be related to different affinities for α_1C isoforms.

2. Inward current evoked by the transfected α₁ subunit was recorded by the patch-clamp technique in the whole-cell configuration.

3. Neutral dihydropyridines (nifedipine, nisoldipine, (+)-PN200-110) were more potent inhibitors of α_1C-b-subunit than of α_1C-a-subunit. This difference was more marked at a holding potential of −100 mV than at −50 mV. SDZ 207-180 (an ionized dihydropyridine) exhibited the same potency on the two isoforms.

4. Pinaverium (ionized non-dihydropyridine derivative) was 2 and 4 fold more potent on α_1C-a than on α_1C-b subunit at Vh of −100 mV and −50 mV, respectively. Effects of verapamil were identical on the two isoforms at both voltages.

5. [³H]-(+)-PN 200-110 binding experiments showed that neutral dihydropyridines had a higher affinity for the α_1C-b than for the α_1C-a subunit. SDZ 207-180 had the same affinity for the two isoforms and pinaverium had a higher affinity for the α_1C-a subunit than for the α_1C-b subunit.

6. These results indicate marked differences among Ca²⁺ channel blockers in their selectivity for the α_1C-a and α_1C-b subunits of the Ca²⁺ channel.

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