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Volume 17, Number 9, Issue of May 1, 1997 pp. 3002-3013
Copyright ©1997 Society for Neuroscience

Preferential Interaction of -Conotoxins with Inactivated N-type Ca²⁺ Channels

Received Nov. 28, 1996; revised Feb. 18, 1997; accepted Feb. 20, 1997.

Jonathan W. Stocker¹, Laszlo Nadasdi², Richard W. Aldrich³, and Richard W. Tsien¹

¹ Department of Molecular and Cellular Physiology and ² Howard Hughes Medical Institute, Stanford University, Stanford, California 94305 and ³ Neurex Corporation, Menlo Park, California 94025

The selective block of N-type Ca²⁺ channels by -conotoxins has been a hallmark of these channels, critical in delineating their biological roles and molecular characteristics. Here we report that the -conotoxin-channel interaction depends strongly on channel gating. N-type channels (_1B, ₂, and ₁) expressed in Xenopus oocytes were blocked with a variety of -conotoxins, including -CTx-GVIA, -CTx-MVIIA, and SNX-331, a derivative of -CTx-MVIIC. Changes in holding potential (HP) markedly altered the severity of toxin block and the kinetics of its onset and removal. Notably, strong hyperpolarization renders -conotoxin block completely reversible. These effects could be accounted for by a modulated receptor model, in which toxin dissociation from the inactivated state is ~60-fold slower than from the resting state. Because -conotoxins act exclusively outside cells, our results suggest that voltage-dependent inactivation of Ca²⁺ channels must be associated with an externally detectable conformational change.

Key words: calcium channel; -conotoxin; inactivation; voltage-dependent binding; modulated receptor hypothesis; N-type

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