The auxiliary subunit [[gamma].sub.1] of the skeletal muscle L-type [Ca.sup.2+] channel is an endogenous [Ca.sup.2+] antagonist

[Ca.sup.2+] 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 [Ca.sup.2+] channels (dihydropyridine receptors, DHPRs) are specialized for the remote voltage control of type 1 ryanodine receptors (RyR1) to release stored [Ca.sup.2+]. The skeletal muscle-specific 1, subunit of the DHPR ([[gamma].sub.1]) down-modulates availability by altering its steady state voltage dependence. The effect resembles the action of certain [Ca.sup.2+] antagonistic drugs that are thought to stabilize inactivated states of the DHPR. In the present study we investigated the cross influence of [[gamma].sub.1] and [Ca.sup.2+] antagonists by using wild-type ([gamma]+/+) and [[gamma].sub.1] knockout ([gamma]-/-) mice. We studied voltage-dependent gating of both L-type [Ca.sup.2+] current and [Ca.sup.2+] release and the allosteric modulation of drug binding. We found that 10 [micro]M diltiazem, a benzothiazepine drug, more than compensated for the reduction in high-affinity binding of the dihydropyridine agent isradipine caused by [[gamma].sub.1] elimination; 5 [micro]M devapamil [(-)D888], a phenylalkylamine [Ca.sup.2+] antagonist, approximately reversed the right-shifted voltage dependence of availability and the accelerated recovery kinetics of [Ca.sup.2+] current and [Ca.sup.2+] release. Moreover, the presence of [[gamma].sub.1] altered the effect of D888 on availability and strongly enhanced its impact on recovery kinetics demonstrating that [[gamma].sub.1] and the drug do not act independently of each other. We propose that the [[gamma].sub.1] subunit of the DHPR functions as an endogenous [Ca.sup.2+] antagonist whose task may be to minimize [Ca.sup.2+] entry and [Ca.sup.2+] release under stress-induced conditions favoring plasmalemma depolarization.