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<p>What is the molecular origin of voltage&#xa0;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<sub>V</sub>1.1). In turn, the conformational changes in Ca<sub>V</sub>1.1 propagate to and activate intracellular ryanodine receptors (RyR1), causing Ca<sup>2+</sup> release and contraction. The Ca<sub>V</sub>1.1 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 Ca<sup>2+</sup> 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 Ca<sup>2+</sup> release and contraction.</p>

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The molecular transition that confers voltage dependence to muscle contraction

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月24日

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  • Marina Angelini,
  • Nicoletta Savalli,
  • Federica Steccanella,
  • Savana Maxfield,
  • Serena Pozzi,
  • Marino DiFranco,
  • Stephen C. Cannon,
  • Antonios Pantazis,
  • Riccardo Olcese

摘要

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 (CaV1.1). In turn, the conformational changes in CaV1.1 propagate to and activate intracellular ryanodine receptors (RyR1), causing Ca2+ release and contraction. The CaV1.1 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.