The four voltage-sensing domains of T-type calcium channels activate near the resting membrane potential.
basic_science · Level V
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- Record sourced from PubMed, PMID 42143043.
- Also identified by DOI 10.1038/s41467-026-73077-1.
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Abstract
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.