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

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.