Wittekindt B, Malany S, Schemm R, Otvos L, Maccecchini M L, Laube B, Betz H
Department of Neurochemistry, Max-Planck-Institute for Brain Research, Deutschordenstrasse 46, 60528, Frankfurt/Main, Germany.
Neuropharmacology. 2001 Nov;41(6):753-61. doi: 10.1016/s0028-3908(01)00112-5.
Conantokin-G (Con-G), a gamma-carboxylglutamate (Gla) containing peptide derived from the venom of the marine cone snail Conus geographus, acts as a selective and potent inhibitor of N-methyl-D-aspartate (NMDA) receptors. Here, the effect of Con-G on recombinant NMDA receptors carrying point mutations within the glycine and glutamate binding pockets of the NR1 and NR2B subunits was studied using whole-cell voltage-clamp recording from cRNA injected Xenopus oocytes. At wild-type receptors, glutamate-induced currents were inhibited by Con-G in a dose-dependent manner at concentrations of 0.1-100 microM. Substitution of selected residues within the NR2B subunit reduced the inhibitory potency of Con-G, whereas similar mutations in the NR1 subunit had little effect. These results indicate a selective interaction of Con-G with the glutamate binding pocket of the NMDA receptor. Homology-based molecular modeling of the glutamate binding region based on the known structure of the glutamate binding site of the AMPA receptor protein GluR2 suggests how selected amino acid side chains of NR2B might interact with specific residues of Con-G.
芋螺毒素G（Con-G）是一种从地纹芋螺毒液中提取的含γ-羧基谷氨酸（Gla）的肽，它是N-甲基-D-天冬氨酸（NMDA）受体的一种选择性强效抑制剂。在此，利用从注射了cRNA的非洲爪蟾卵母细胞进行全细胞膜片钳记录，研究了Con-G对在NR1和NR2B亚基的甘氨酸和谷氨酸结合口袋内携带点突变的重组NMDA受体的影响。在野生型受体中，在0.1 - 100微摩尔浓度下，Con-G以剂量依赖方式抑制谷氨酸诱导的电流。NR2B亚基内特定残基的替换降低了Con-G的抑制效力，而NR1亚基中的类似突变影响较小。这些结果表明Con-G与NMDA受体的谷氨酸结合口袋存在选择性相互作用。基于AMPA受体蛋白GluR2的谷氨酸结合位点的已知结构，对谷氨酸结合区域进行基于同源性的分子建模，提示了NR2B的选定氨基酸侧链可能如何与Con-G的特定残基相互作用。
