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

Abstract Low-voltage-activated (LVA, T-type, or Ca V 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 V 3.1-channels precedes opening in voltage, solving the longstanding conundrum. We also uncover confounding effects of La 3+ (used for gating-current measurements) on VSD function and clarify the role of distinct LVA-channel structure S6 Cyto . Ca V 3.1-VSDs operate within a narrow voltage-range, resembling the VSDs of related Na V -channels more than those of other Ca V -channels. Likely, Na V -like VSDs emerge before sodium selectivity.

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Publication Details

Journal
Nature Communications
Published
2026-05-16
DOI
https://doi.org/10.1038/s41467-026-73077-1
Primary Topic
Ion channel regulation and function
Type
article
Field-Weighted Citation Impact
0.00

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article

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

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Nature Communications
Ion channel regulation and function
article

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

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

Abstract

Abstract Low-voltage-activated (LVA, T-type, or Ca V 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 V 3.1-channels precedes opening in voltage, solving the longstanding conundrum. We also uncover confounding effects of La 3+ (used for gating-current measurements) on VSD function and clarify the role of distinct LVA-channel structure S6 Cyto . Ca V 3.1-VSDs operate within a narrow voltage-range, resembling the VSDs of related Na V -channels more than those of other Ca V -channels. Likely, Na V -like VSDs emerge before sodium selectivity.

Nature Communications
Linköping University (SE), University of California, Los Angeles (US), University of Valparaíso (CL)
Hjärnfonden, Knut och Alice Wallenbergs Stiftelse, Vetenskapsrådet, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences
Openalex Percentile: Top 7%
Ion channel regulation and function
DOIOpen Access PDFOpenAlex
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