The molecular transition that confers voltage dependence to muscle contraction

What is the molecular origin of voltage dependence in skeletal muscle excitation-contraction? Cholinergic transmission to the muscle fiber triggers action potentials, which are sensed by voltage-gated L-type calcium channels (Ca_V1.1). In turn, the conformational changes in Ca_V1.1 propagate to and activate intracellular ryanodine receptors (RyR1), causing Ca²⁺ release and contraction. The Ca_V1.1 channel has four voltage-sensing domains (VSD-I to -IV) with diverse voltage-sensing properties, so the identity of VSD(s) responsible for conferring voltage dependence to RyR1 opening, is unknown. Using voltage-clamp fluorometry, we show that only VSD-III possesses kinetic, voltage-dependent and pharmacological properties consistent with skeletal-muscle excitability and Ca²⁺ release. We propose that the earliest voltage-dependent event in the excitation-contraction process is the structural rearrangement of VSD-III that propagates to RyR1 to initiate Ca²⁺ release and contraction.