ArticleThe Journal of general physiology2021
The distinct role of the four voltage sensors of the skeletal CaV1.1 channel in voltage-dependent activation.
Article in The Journal of general physiology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers, 1 of them a synthesis that pooled it.
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Who cites it
23 citing papers in PubMed, 1 synthesis or guideline pooled it, 35 citations in OpenAlex.
- Pharmacological insights intoFrontiers in pharmacology · 2025Pooled it
- Pathogenic CaCommunications biology · 2026Article
- The four voltage-sensing domains of T-type calcium channels activate near the resting membrane potential.Nature communications · 2026Article
- Voltage-sensing domains: structural and functional diversity.European biophysics journal : EBJ · 2025Review
- Voltage-sensor gating charge interactions bimodally regulate voltage dependence and kinetics of calcium channel activation.The Journal of general physiology · 2025Article
- The molecular transition that confers voltage dependence to muscle contraction.Nature communications · 2025Article
- A rich conformational palette underlies human CaNature communications · 2025Article
- Voltage sensors.Molecular pharmacology · 2025Review
- Article
- Voltage-dependent G-protein regulation of CaScience advances · 2024Article
- CaNature communications · 2024Article
- Asymmetric contribution of a selectivity filter gate in triggering inactivation of CaV1.3 channels.The Journal of general physiology · 2024Article
- Advances in CaChannels (Austin, Tex.) · 2023Review
- Fifty years of gating currents and channel gating.The Journal of general physiology · 2023Review
- Functional Characterization of Four Known Cav2.1 Variants Associated with Neurodevelopmental Disorders.Membranes · 2023Article
- Case report: A novelFrontiers in neurology · 2023Article
- Calcium signaling in neurodevelopment and pathophysiology of autism spectrum disorders.Molecular biology reports · 2022Review
- Excitation-contraction coupling in cardiac, skeletal, and smooth muscle.The Journal of general physiology · 2022Article
- Superfast excitation-contraction coupling in adult zebrafish skeletal muscle fibers.The Journal of general physiology · 2022Article
- Voltage-dependent CaAmerican journal of physiology. Cell physiology · 2022Article
Corrections and comments
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Authors and funding
10 authors at 1 institution in 2 countries.
Funding
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 CaV1.1 channels to inherit voltage sensitivity. Using an opto-electrophysiological approach, we resolved the excitation-driven molecular events controlling both CaV1.1 and RYR1 activations, reported as fluorescence changes. We discovered that each of the four human CaV1.1 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 CaV1.1 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 CaV1.1 activation was also confirmed using a naturally occurring, charge-neutralizing mutation in VSD-I (R174W). This mutation abolished CaV1.1 current at physiological membrane potentials by impairing VSD-I activation without affecting the other VSDs. Using a structurally relevant allosteric model of CaV activation, which accounted for both time- and voltage-dependent properties of CaV1.1, to predict VSD-pore coupling energies, we found that VSD-I contributed the most energy (~75 meV or ∼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 ∼1 kT). This study settles the longstanding question of how CaV1.1, 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 CaV1.1 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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.