The distinct role of the four voltage sensors of the skeletal Ca(V)1.1 channel in voltage-dependent activation
JOURNAL OF GENERAL PHYSIOLOGY(2021)
Abstract
Initiation of skeletal muscle contraction is triggered by rapid activation of RYR1 channels in response to sarcolemmal depolarization. RYR1 is intracellular and has no voltage-sensing structures, but it is coupled with the voltage-sensing apparatus of Ca(V)1.1 channels to inherit voltage sensitivity. Using an opto-electrophysiological approach, we resolved the excitation-driven molecular events controlling both Ca(V)1.1 and RYR1 activations, reported as fluorescence changes. We discovered that each of the four human Ca(V)1.1 voltage-sensing domains (VSDs) exhibits unique biophysical properties: VSD-I time-dependent properties were similar to ionic current activation kinetics, suggesting a critical role of this voltage sensor in Ca(V)1.1 activation; VSD-II, VSD-III, and VSD-IV displayed faster activation, compatible with kinetics of sarcoplasmic reticulum Ca2+ release. The prominent role of VSD-I in governing Ca(V)1.1 activation was also confirmed using a naturally occurring, chargeneutralizing mutation in VSD-I (R174W). This mutation abolished Ca(V)1.1 current at physiological membrane potentials by impairing VSD-I activation without affecting the other VSDs. Using a structurally relevant allosteric model of Ca-V activation, which accounted for both time- and voltage-dependent properties of Ca(V)1.1, to predict VSD-pore coupling energies, we found that VSD-I contributed the most energy (similar to 75 meV or similar to 3 kT) toward the stabilization of the open states of the channel, with smaller (VSD-IV) or negligible (VSDs II and III) energetic contribution from the other voltage sensors (<25 meV or similar to 1 kT). This study settles the longstanding question of how Ca(V)1.1, a slowly activating channel, can trigger RYR1 rapid activation, and reveals a new mechanism for voltage-dependent activation in ion channels, whereby pore opening of human Ca(V)1.1 channels is primarily driven by the activation of one voltage sensor, a mechanism distinct from that of all other voltage-gated channels.
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Key words
voltage sensors,voltage-dependent
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