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bioRxiv · 10.1101/2024.06.29.600263

Electrical and G-protein Regulation of CaV2.2 (N-type) Channels

Nilsson, M.·Wang, K.·Minguez-Vinas, T.·Angelini, M.·Berglund, S.·Olcese, R.·Pantazis, A.
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Abstract

How G-proteins inhibit N-type, voltage-gated, calcium-selective channels (CaV2.2) during presynaptic inhibition is a decades-old question. G-proteins G{beta}{gamma} bind to intracellular CaV2.2 regions, but the inhibition is voltage-dependent. Using the hybrid electrophysiological and optical approach voltage-clamp fluorometry, we show that G{beta}{gamma} acts by selectively inhibiting a subset of the four different CaV2.2 voltage-sensor domains (VSDs I-IV). During regular "willing" gating, VSDs I and IV activation resemble pore opening, VSD III activation is hyperpolarized, and VSD II appears unresponsive to depolarization. In the presence of G{beta}{gamma}, CaV2.2 gating is "reluctant": pore opening and VSD-I activation are strongly and proportionally inhibited, VSD IV is modestly inhibited while VSD III is not. We propose that G{beta}{gamma} inhibition of VSD-I and -IV underlies reluctant CaV2.2 gating and subsequent presynaptic inhibition.

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Nilsson, M., Wang, K., Minguez-Vinas, T., Angelini, M., Berglund, S., Olcese, R., Pantazis, A.. 2024-06-30. Electrical and G-protein Regulation of CaV2.2 (N-type) Channels. https://doi.org/10.1101/2024.06.29.600263

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