The auxiliary subunit γ1 of the skeletal muscle L-type Ca2+ channel is an endogenous Ca2+ antagonist

Ca2+ channels play crucial roles in cellular signal transduction and are important targets of pharmacological agents. They are also associated with auxiliary subunits exhibiting functions that are still incompletely resolved. Skeletal muscle L-type Ca2+ channels (dihydropyridine receptors, DHPRs) are specialized for the remote voltage control of type 1 ryanodine receptors (RyR1) to release stored Ca2+. The skeletal muscle-specific γ subunit of the DHPR (γ1) down-modulates availability by altering its steady state voltage dependence. The effect resembles the action of certain Ca2+ antagonistic drugs that are thought to stabilize inactivated states of the DHPR. In the present study we investigated the cross influence of γ1 and Ca2+ antagonists by using wild-type (γ+/+) and γ1 knockout (γ−/−) mice. We studied voltage-dependent gating of both L-type Ca2+ current and Ca2+ release and the allosteric modulation of drug binding. We found that 10 μM diltiazem, a benzothiazepine drug, more than compensated for the reduction in high-affinity binding of the dihydropyridine agent isradipine caused by γ1 elimination; 5 μM devapamil [(−)D888], a phenylalkylamine Ca2+ antagonist, approximately reversed the right-shifted voltage dependence of availability and the accelerated recovery kinetics of Ca2+ current and Ca2+ release. Moreover, the presence of γ1 altered the effect of D888 on availability and strongly enhanced its impact on recovery kinetics demonstrating that γ1 and the drug do not act independently of each other. We propose that the γ1 subunit of the DHPR functions as an endogenous Ca2+ antagonist whose task may be to minimize Ca2+ entry and Ca2+ release under stress-induced conditions favoring plasmalemma depolarization