Structural rigidity of the I-II loop couples Ca_V β anchoring to Ca_V2.2 gating modes.

Authors

Jin-Nyeong Woo, Jung-Eun Kim, Byung-Chang Suh

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 30. Pages e2602744123. Jul 28, 2026. Epub Jul 22, 2026.

Abstract

The auxiliary β subunits of voltage-gated Ca²⁺ (Ca_V) channels are fundamental regulators of channel gating and neuronal excitability. While the subcellular localization of β subunits is known to influence current density and inactivation, the precise kinetic mechanism by which they differentially modulate channel opening and closing remains elusive. Here, we report a kinetic paradox in Ca_V2.2 channels: membrane-anchored β subunits decelerate current decay during depolarization yet accelerate tail deactivation upon repolarization, whereas cytosolic β subunits promote rapid decay but prolong deactivation. Using quantitative kinetic analysis and Markov state modeling, we demonstrate that macroscopic current decay is not solely a monolithic irreversible inactivation process but a composite of irreversible inactivation and a reversible transition to a nonconducting state. We reveal that membrane-anchored β subunits suppress the transition to this reversible nonconducting state, thereby maintaining the open state, while facilitating a rapid return from the nonconducting state to prevent kinetic trapping. Furthermore, by manipulating the linker length of β subunits and engineering the I-II loop hinge region (R370), we identify that the physical proximity of the β subunit to the plasma membrane, coupled with the structural rigidity of the I-II loop, acts as a mechanical determinant that governs this gating pathway selection. Our findings provide a unified gating model in which the β subunit fine-tunes the dynamic equilibrium between conducting and nonconducting states via mechanical constraint on the channel complex, offering a comprehensive resolution to the distinct regulation of Ca_V2.2 kinetics.

PMID:
42485390
Bibliographic data and abstract were imported from PubMed on 23 Jul 2026.

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