µ-Theraphotoxin Pn3a inhibition of Ca_V3.3 channels reveals a novel isoform-selective drug binding site.

ABSTRACT: Low voltage-activated calcium currents are mediated by T-type calcium channels Ca_V3.1, Ca_V3.2, and Ca_V3.3, which modulate a variety of physiological processes including sleep, cardiac pace-making, pain, and epilepsy. Ca_V3 isoforms' biophysical properties, overlapping expression, and lack of subtype-selective pharmacology hinder the determination of their specific physiological roles in health and disease. We have identified μ-theraphotoxin Pn3a as the first subtype-selective spider venom peptide inhibitor of Ca_V3.3, with >100-fold lower potency against the other T-type isoforms. Pn3a modifies Ca_V3.3 gating through a depolarizing shift in the voltage dependence of activation thus decreasing Ca_V3.3-mediated currents

SUBMITTER: McArthur JR 

PROVIDER: S-EPMC9342953 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature