Preferential interaction of omega-conotoxins with inactivated N-type Ca2+ channels.
The selective block of N-type Ca2+ channels by omega-conotoxins has been a hallmark of these channels, critical in delineating their biological roles and molecular characteristics. Here we report that the omega-conotoxin-channel interaction depends strongly on channel gating. N-type channels (alpha1B, alpha2, and beta1) expressed in Xenopus oocytes were blocked with a variety of omega-conotoxins, including omega-CTx-GVIA, omega-CTx-MVIIA, and SNX-331, a derivative of omega-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 omega-conotoxin block completely reversible. These effects could be accounted for by a modulated receptor model, in which toxin dissociation from the inactivated state is approximately 60-fold slower than from the resting state. Because omega-conotoxins act exclusively outside cells, our results suggest that voltage-dependent inactivation of Ca2+ channels must be associated with an externally detectable conformational change.
Stocker
J W
JW
Department of Molecular and Cellular Physiology, Stanford University, Stanford, California 94305, USA.
Nadasdi
L
L
Aldrich
R W
RW
Tsien
R W
RW
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D010455:Peptides / Q000494:pharmacology*; D014982:Xenopus laevis; D020866:omega-Conotoxin GVIA; D020960:omega-Conotoxins
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D010455:Peptides; D020960:omega-Conotoxins; C075851:omega-conotoxin-MVIIC; D020866:omega-Conotoxin GVIA