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<p>Low-voltage-activated (LVA, T-type, or Ca<sub>V</sub>3), calcium-selective channels open in response to modest depolarizations, just above the resting membrane potential, supporting neuronal burst-firing patterns and spontaneous firing in cardiac pacemaker cells. How LVA-channels open at low voltages is unclear: traditional gating-current experiments suggest that LVA-channel voltage-sensing domains (VSDs) paradoxically require stronger depolarization to activate than pore opening. Using voltage-clamp fluorometry, we find that the activation of all four VSDs in human Ca<sub>V</sub>3.1-channels precedes opening in voltage, solving the longstanding conundrum. We also uncover confounding effects of La<sup>3+</sup> (used for gating-current measurements) on VSD function and clarify the role of distinct LVA-channel structure S6<sup>Cyto</sup>. Ca<sub>V</sub>3.1-VSDs operate within a narrow voltage-range, resembling the VSDs of related Na<sub>V</sub>-channels more than those of other Ca<sub>V</sub>-channels. Likely, Na<sub>V</sub>-like VSDs emerge before sodium selectivity.</p>

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The four voltage-sensing domains of T-type calcium channels activate near the resting membrane potential

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月16日

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  • Marina Angelini,
  • Moira McVicar,
  • Savana Maxfield,
  • Milosz Sokolowski,
  • Sanjana Narang,
  • Kyle Scranton,
  • S. Suheda Yasarbas,
  • Nicoletta Savalli,
  • Scott A. John,
  • Andreas Schwingshackl,
  • Alan Neely,
  • Antonios Pantazis,
  • Michela Ottolia,
  • Riccardo Olcese

摘要

Low-voltage-activated (LVA, T-type, or CaV3), calcium-selective channels open in response to modest depolarizations, just above the resting membrane potential, supporting neuronal burst-firing patterns and spontaneous firing in cardiac pacemaker cells. How LVA-channels open at low voltages is unclear: traditional gating-current experiments suggest that LVA-channel voltage-sensing domains (VSDs) paradoxically require stronger depolarization to activate than pore opening. Using voltage-clamp fluorometry, we find that the activation of all four VSDs in human CaV3.1-channels precedes opening in voltage, solving the longstanding conundrum. We also uncover confounding effects of La3+ (used for gating-current measurements) on VSD function and clarify the role of distinct LVA-channel structure S6Cyto. CaV3.1-VSDs operate within a narrow voltage-range, resembling the VSDs of related NaV-channels more than those of other CaV-channels. Likely, NaV-like VSDs emerge before sodium selectivity.