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Low voltage-activated calcium currents are mediated by T-type calcium channels Ca V 3.1, Ca V 3.2, and Ca V 3.3, which modulate a variety of physiological processes including sleep, cardiac pace-making, pain, and epilepsy. Ca V 3 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 V 3.3, with &gt;100-fold lower potency against the other T-type isoforms. Pn3a modifies Ca V 3.3 gating through a depolarizing shift in the voltage dependence of activation thus decreasing Ca V 3.3-mediated currents in the normal range of activation potentials. Paddle chimeras of K V 1.7 channels bearing voltage sensor sequences from all four Ca V 3.3 domains revealed preferential binding of Pn3a to the S3-S4 region of domain II (Ca V 3.3 DII ). This novel T-type channel pharmacological site was explored through computational docking simulations of Pn3a, site-directed mutagenesis, and full domain II swaps between Ca V 3 channels highlighting it as a subtype-specific pharmacophore. This research expands our understanding of T-type calcium channel pharmacology and supports the suitability of Pn3a as a molecular tool in the study of the physiological roles of Ca V 3.3 channels.

µ-Theraphotoxin Pn3a inhibition of Ca V 3.3 channels reveals a novel isoform-selective drug binding site