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Vol. 58, Issue 3, 614-623, September 2000
Department of Neurology, University of Utah (S.D.D.), and Cognetix,
Inc. (R.T.M.), Salt Lake City, Utah
Conantokin G (Con G) is a 17-amino-acid peptide antagonist of
N-methyl-D-aspartate (NMDA) receptors
isolated from the venom of the marine cone snail, Conus
geographus. The mechanism of action of Con G has not been well
defined; both competitive and noncompetitive interactions with the
NMDA-binding site have been proposed. In this study the mechanism of
action and subunit selectivity of Con G was examined in whole-cell
voltage-clamp recordings from cultured neurons and in two electrode
voltage-clamp recordings from Xenopus oocytes expressing
recombinant NMDA receptors. Con G was a potent and selective antagonist
of NMDA-evoked currents in murine cortical neurons
(IC50 = 480 nM). The slow onset of Con G block could
be prevented by coapplication with high concentrations of NMDA or of
the competitive antagonist
(RS)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid. Furthermore, in oocytes expressing NR1a/NR2B receptors, Con G produced a rightward shift in the concentration-response curve
for NMDA, providing support for a competitive interaction with the
NMDA-binding site. Con G produced an apparent noncompetitive shift in
the concentration-response curve for spermine potentiation of NMDA
responses, but this was due to spermine-induced enhancement of Con G
block. Spermine produced a similar enhancement of
DL-2-amino-S-phosphopentanoic acid block.
Finally, Con G selectively blocked NMDA receptors containing the NR2B
subunit. These results demonstrate that Con G is a subunit-specific
competitive antagonist of NMDA receptors. The unique subunit
selectivity profile of Con G may explain its favorable in vivo profile
compared with nonselective NMDA antagonists.
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