Biophys J, July 2001, p. 79-88, Vol. 81, No. 1

Interaction of SNX482 with Domains III and IV Inhibits Activation Gating of _1E (Ca_V2.3) Calcium Channels

Emmanuel Bourinet,^* Stephanie C. Stotz, Renée L. Spaetgens, Govindan Dayanithi, José Lemos,^§ Joël Nargeot,^* and Gerald W. Zamponi

 ^*Physiopathologie des Canaux Ioniques, Institut de Génétique Humaine, CNRS UPR1142, 34396 Montpellier Cedex 5, France;  Departments of Physiology and Biophysics and Pharmacology and Therapeutics, Neuroscience Research Group, University of Calgary, Alberta T2N 4N1 Canada;  INSERM U432, Université Montpellier II, cc089, 34095 Montpellier, France; and  ^§Department of Physiology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655 USA

We have investigated the action of SNX482, a toxin isolated from the venom of the tarantula Hysterocrates gigas, on voltage-dependent calcium channels expressed in tsa-201 cells. Upon application of 200 nM SNX482, R-type _1E calcium channels underwent rapid and complete inhibition, which was only poorly reversible upon washout. However, upon application of strong membrane depolarizations, rapid and complete recovery from inhibition was obtained. Tail current analysis revealed that SNX482 mediated an ~70 mV depolarizing shift in half-activation potential, suggesting that the toxin inhibits _1E calcium channels by preventing their activation. Experiments involving chimeric channels combining structural features of _1E and _1C subunits indicated that the presence of the domain III and IV of _1E is a prerequisite for a strong gating inhibition. In contrast, L-type _1C channels underwent incomplete inhibition at saturating concentrations of SNX482 that was paralleled by a small shift in half-activation potential and which could be rapidly reversed, suggesting a less pronounced effect of the toxin on L-type calcium channel gating. We conclude that SNX482 does not exhibit unequivocal specificity for R-type channels, but highly effectively antagonizes their activation.

Biophys J, July 2001, p. 79-88, Vol. 81, No. 1
© 2001 by the Biophysical Society   0006-3495/01/07/79/10  $2.00

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