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Bernhard FLUCHER

Identification of the CaV1.1 voltage-sensing domain controlling skeletal muscle excitation-contraction coupling

The skeletal muscle voltage gated calcium channel CaV1.1 functions as voltage sensor of excitation-contraction (EC) coupling as well as L-type calcium channel. Upon depolarization, CaV1.1 triggers the opening of the RyR1 in the sarcoplasmic reticulum, causing the calcium release essential for skeletal muscle contraction. Upon strong stimulation, CaV1.1 further elicits a calcium current; however, with kinetics and voltage-dependence different from those of EC coupling. We hypothesize that these distinct activation properties result from differential roles of the four CaV1.1 voltage-sensing domains (VSDs). Using site-directed mutagenesis and channel chimeras, we specifically altered the properties of individual VSDs and analyzed the effects of these operations on channel gating and the activation of EC coupling. Whereas mutations in all four VSDs affect the current properties, only mutations in VSD III reduce the amplitude and shift the voltage-dependence of depolarization-induced calcium release. Whereas all four VSD contribute to different aspects of channel gating, only a single VSD is sufficient for controlling EC coupling. Molecular dynamics simulations demonstrate that the pivotal role of VSD III in the EC coupling process is reflected by its rapid and comprehensive state transitions in response to membrane depolarization. Thus, our results demonstrate how the four VSDs of this voltage-gated ion channel divide physiological tasks among each other and reveal structural principles underlying the distinct physiological roles of the four VSD of this voltage-gated calcium channel.