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Updated: May 18, 2026

Functional Site-Directed Fluorometry in Native Cells to Study Skeletal Muscle Excitability
Published on: June 2, 2023
The four voltage-sensing domains of T-type calcium channels activate near the resting membrane potential
Marina Angelini1, Moira McVicar2, Savana Maxfield2
1Division of Molecular Medicine, Department of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. mangelini@ucla.edu.
Abstract:
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.
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