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-Conotoxin GVIA Alters Gating Charge Movement of N-Type (CaV2.2) Calcium Channels

¹Departments of Anesthesiology and ²Pharmacology, Penn State College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania

Submitted 22 September 2008; accepted in final form 23 October 2008

-conotoxin GVIA (CTX) is a specific blocker of N-type calcium (CaV2.2) channels that inhibits neuropathic pain. While the toxin appears to be an open channel blocker, we show that N-channel gating charge movement is modulated. Gating currents were recorded from N-channels expressed along with ß_2a and ₂ subunits in HEK293 cells in external solutions containing either lanthanum and magnesium (La-Mg) or 5 mM Ca²⁺ plus CTX (CTX-Ca). A comparison showed that CTX induced a 10-mV right shift in the gating charge versus voltage (Q-V) relationship, smaller off-gating current time constant ( Q_Off), a lower Q_Off voltage dependence, and smaller on-gating current (Q_On) . We also examined gating current in La-Mg plus CTX and found no significant difference from that in CTX-Ca; this demonstrates that the modulation was induced by the toxin. A model with strongly reduced open-state occupancy reproduced the CTX effect on gating current and showed that the gating modulation alone would inhibit N-current by 50%. This mechanism of N-channel inhibition could be exploited to develop novel analgesics that induce only a partial block of N-current, which may limit some of the side effects associated with the toxin analgesic currently approved for human use (i.e., Prialt).