The role of CaV1.1 VSDs: fast and slow VSDs control R Y R1 and CaV1.1 activation, respectively. (A) Scheme depicting the main players in the skeletal muscle EC coupling process: RYR1 (orange) is unable to sense depolarizations of the sarcolemma because of its localization in the intracellular SR. RYR1 is in physical contact (directly or via auxiliary proteins) with CaV1.1 channel (red), which is inserted in the sarcolemma and confers voltage dependence to RYR1. At rest, both channels are closed, and the skeletal muscle is relaxed. (B and C) Upon depolarization, the VSDs of CaV1.1 channels (blue and green) rearrange. VSD-II and VSD-III kinetics are compatible with the SR Ca2+-release time course; thus, we propose that their movement mechanically and rapidly propagates to RYR1 (B), allowing for SR Ca2+-release: VSD-II and/or VSD-III constitute the voltage sensor(s) of skeletal muscle contraction. On the other hand, VSD-I (blue) activates with slower kinetics compatible with CaV1.1 opening. Indeed, combining fluorometry, mutagenesis, and mathematical modeling, we demonstrated that VSD-I contributes the most energy to CaV1.1 activation (C). While each homotetrameric RYR1 interacts with four CaV1.1 channels, for clarity, the cartoon only depicts one CaV1.1 interacting with one monomer of RYR1. This scheme was created with http://www.BioRender.com.