TY - JOUR T1 - Conantokin G Is an NR2B-Selective Competitive Antagonist of<em>N</em>-Methyl-<span class="sc">d</span>-aspartate Receptors JF - Molecular Pharmacology JO - Mol Pharmacol SP - 614 LP - 623 DO - 10.1124/mol.58.3.614 VL - 58 IS - 3 AU - Sean D. Donevan AU - R. Tyler McCabe Y1 - 2000/09/01 UR - http://molpharm.aspetjournals.org/content/58/3/614.abstract N2 - Conantokin G (Con G) is a 17-amino-acid peptide antagonist ofN-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 ofdl-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. ER -