Subunit-dependent inhibition of recombinant rodent N-methyl-D-aspartate receptors by a HIV-1 glycoprotein 120 derived peptide

Considerable evidence suggests that low (picomolar) concentrations of the H IV-1 envelope glycoprotein gp120 induce neuronal cell death by stimulating the release of microglial toxins, which in turn activate N-methyl-D-asparta te (NMDA) receptors. Conversely, high (micromolar) concentrations of gp120 have been reported to directly inhibit NMDA receptor-mediated currents and do not induce neurotoxicity. Here we show that micromolar concentrations of a synthetic peptide corresponding to the VS-loop of gp120 (VS-pep) inhibit ed agonist responses of recombinant heteromeric rodent NMDA receptors expre ssed in Xenopus laevis oocytes by decreasing their apparent glycine affinit y. Different combinations of NMDA receptor subunits displayed differential sensitivities to inhibition by VS-pep, with a potency rank order of NR1/2B > NR1/2D > NR1/2C greater than or equal to NR1/2A. Our observations may pro vide an explanation for the reduced neurotoxicity of high doses of gp120 in cell cultures and may be useful for tt-le pharmacological discrimination o f NMDA receptor subtypes. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.