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NEUROPHARMACOLOGY

Inhibition of High Voltage-Activated Calcium Channels by Spider Toxin PnTx3-6

Biotechnology Laboratory, University of British Columbia, Vancouver, British Columbia, Canada (L.B.V., M.E.H., E.G., A.S., T.P.S.); Laboratório de Neurofarmacologia, Departamento de Farmacologia, Instituto de Ciências Biológicas-Universidade Federal de Minas Gerais, Belo Horizonte, Brazil (L.B.V., C.K., M.V.G.); and Centro de Pesquisa Professor Carlos R. Diniz, Fundação Ezequiel Dias, Belo Horizonte, Brazil (M.N.C., M.R.)

Animal peptide toxins have become powerful tools to study structure-function relationships and physiological roles of voltage-activated Ca²⁺ channels. In the present study, we investigated the effects of PnTx3-6, a neurotoxin purified from the venom of the spider Phoneutria nigriventer on cloned mammalian Ca²⁺ channels expressed in human embryonic kidney 293 cells and endogenous Ca²⁺ channels in N18 neuroblastoma cells. Whole-cell patch-clamp measurements indicate that PnTx3-6 reversibly inhibited L-(_1C/Ca_v1.2), N-(_1B/Ca_v2.2), P/Q-(_1A/Ca_v2.1), and R-(_1E/Ca_v2.3) type channels with varying potency (_1B > _1E > _1A > _1C) and IC₅₀ values of 122, 136, 263, and 607 nM, respectively. Inhibition occurred without alteration of the kinetics or the voltage dependence of the exogenously expressed Ca²⁺ channels. In N18 cells, PnTx3-6 exhibited highest potency against N-type (conotoxin-GVIA-sensitive) current. In contrast to its effects on high voltage-activated Ca²⁺ channels subtypes, application of 1 µM PnTx3-6 did not affect _1G/Ca_v3.1 T-type Ca²⁺ channels. Based on our study, we suggest that PnTx3-6 acts as a -toxin that targets high voltage-activated Ca²⁺ channels, with a preference for the Ca_v2 subfamily (N-, P/Q-, and R-types).

Address correspondence to: Dr. Marcus Vinícius Gomez, Departamento de Farmacologia, ICB-Universidade Federal de Minas Gerais, Avenida Antonio Carlos, 6627, Belo Horizonte, MG 30270-901 Brazil. E-mail: gomez{at}icb.ufmg.br

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				N. Martin-Moutot, P. Mansuelle, G. Alcaraz, R. G. D. Santos, M. N. Cordeiro, M. E. De Lima, M. Seagar, and C. Van Renterghem Phoneutria nigriventer Toxin 1: A Novel, State-Dependent Inhibitor of Neuronal Sodium Channels That Interacts with {micro} Conotoxin Binding Sites Mol. Pharmacol., June 1, 2006; 69(6): 1931 - 1937. [Abstract] [Full Text] [PDF]