The Auxiliary Subunit γ₁ of the Skeletal Muscle L-Type Ca²⁺ Channel Is an Endogenous Ca²⁺ Antagonist

• Published in: Proceedings of the National Academy of Sciences - PNAS 2007-11, Vol.104 (45), p.17885-17890
• Main Authors: Andronache, Zoita, Ursu, Daniel, Lehnert, Simone, Freichel, Marc, Flockerzi, Veit, Melzer, Werner
• Format: Article
• Language: English
• Subjects: Biological Sciences; Depolarization; Dihydropyridines; Drug dependence; Drug interactions; Electric potential; Kinetics; Muscle fibers; Paralysis; Receptors; Skeletal muscle
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0704340104

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.