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Wang K, Nilsson M, Angelini M, Olcese R, Elinder F, Pantazis A
Nat Commun 16 (1) 3815 [2025-04-23; online 2025-04-23]
Depolarization-evoked opening of CaV2.1 (P/Q-type) Ca2+-channels triggers neurotransmitter release, while voltage-dependent inactivation (VDI) limits channel availability to open, contributing to synaptic plasticity. The mechanism of CaV2.1 response to voltage is unclear. Using voltage-clamp fluorometry and kinetic modeling, we optically track and physically characterize the structural dynamics of the four CaV2.1 voltage-sensor domains (VSDs). The VSDs are differentially sensitive to voltage changes, both brief and long-lived. VSD-I seems to directly drive opening and convert between two modes of function, associated with VDI. VSD-II is apparently voltage-insensitive. VSD-III and VSD-IV sense more negative voltages and undergo voltage-dependent conversion uncorrelated with VDI. Auxiliary β-subunits regulate VSD-I-to-pore coupling and VSD conversion kinetics. Hence, the central role of CaV2.1 channels in synaptic release, and their contribution to plasticity, memory formation and learning, can arise from the voltage-dependent conformational changes of VSD-I.
PubMed 40268901
DOI 10.1038/s41467-025-58884-2
Crossref 10.1038/s41467-025-58884-2
pmc: PMC12019389
pii: 10.1038/s41467-025-58884-2