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The Journal of Neuroscience, October 15, 2002, 22(20):8884-8890

Rapid and Reversible Block of N-Type Calcium Channels (Ca_V 2.2) by -Conotoxin GVIA in the Absence of Divalent Cations

Haoya Liang and Keith S. Elmslie

Department of Physiology, Tulane University Health Science Center, New Orleans, Louisiana 70112

-Conotoxin GVIA (CGVIA) has been reported to be an irreversible blocker of N-type calcium channels (Ca_V 2.2). However, recent studies have demonstrated that the CGVIA off-rate is correlated with divalent cation concentration, because increasing [Ba²⁺]_o accelerated the recovery from CGVIA block. This predicts that the dissociation of CGVIA from N-channels will be negligible in the absence of divalent cations. Surprisingly, we find that CGVIA block is rapidly reversible in divalent cation-free (0 Ba²⁺) external solutions in which current was carried by MA⁺. The recovery followed a single-exponential time course with  = 31 sec. Isochronic measurements showed that, at 2 min after the removal of toxin, current returned to 86% of control in 0 Ba²⁺ compared with 19% in 3 mM Ba²⁺. The off-rate of CGVIA from N-channels was dependent on [Ba²⁺]_o, because, at an intermediate concentration (3 µM Ba²⁺), N-current recovered with  = 64 sec, significantly slower than that in 0 Ba²⁺ but faster than in 3 mM Ba²⁺. Recovery from CGVIA block was also observed when Cs⁺ or Na⁺ carried the current in divalent cation-free conditions. The off-rate was sensitive to [Ba²⁺]_o only during washout, because current recovered slowly in the presence of 3 mM Ba²⁺, even after it was blocked in 0 Ba²⁺. Assuming that the toxin is a pore blocker, our findings are consistent with a model in which Ba²⁺ interacts at a site on the extracellular surface of the channel to regulate CGVIA dissociation from N-channels.

Key words: bullfrog; sympathetic neurons; patch-clamp; monovalent cations; toxin; off-rate; on-rate

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22208884-07$05.00/0

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