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

Yarotskyy V, Elmslie KS. omega-conotoxin GVIA alters gating charge movement of N-type (CaV2.2) calcium channels. J Neurophysiol 101: 332-340, 2009. First published October 29, 2008; doi:10.1152/jn.91064.2008. omega-conotoxin GVIA (omega 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 beta(2a) and alpha(2)delta subunits in HEK293 cells in external solutions containing either lanthanum and magnesium (La-Mg) or 5 mM Ca2+ plus omega CTX (omega CTX-Ca). A comparison showed that omega CTX induced a 10-mV right shift in the gating charge versus voltage (Q-V) relationship, smaller off-gating current time constant (tau Q(Off)), a lower tau Q(Off) voltage dependence, and smaller on-gating current (Q(On)) tau. We also examined gating current in La-Mg plus omega CTX and found no significant difference from that in omega CTX-Ca; this demonstrates that the modulation was induced by the toxin. A model with strongly reduced open-state occupancy reproduced the omega 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).