The human immunodeficiency virus-1 envelope protein gp120 binds through its V3 sequence to the glycine site of N-methyl-D-aspartate receptors mediating noradrenaline release in the hippocampus.

Recent results show that the HIV-1 protein gp120 can enhance N-methyl-D-aspartate receptor-mediated release of noradrenaline from CNS nerve endings. We now investigate the mechanism of this action, including the structural determinants of the gp120 effect and the nature of its binding sites. The N-methyl-D-aspartate-evoked release of [3H]noradrenaline from rat hippocampal synaptosomes was potentiated similarly by gp120 and gp160; gp41 was ineffective. The regions of gp120 involved appear to be outside the CD4-binding domain of the protein, because gp120 retained its activity after pretreatment with N-carbomethoxycarbonyl-D-prolyl-D-phenylalanine, a compound known to inhibit binding of gp120 to CD4 receptors. Moreover, sequences of gp120 critical for binding to CD4 did not mimic the effect of gp120. Preincubation of synaptosomes with anti-galactocerebroside antibodies did not affect gp120 activity. The protein effect was retained by peptides mimicking its V3 sequence, including the cyclic V3 "universal peptide" and the linear V3 sequence BRU-C-34-A, but not RP-135 (a central portion of BRU-C-34-A). The block of the N-methyl-D-aspartate-induced [3H]noradrenaline release by 7-chlorokynurenate, an antagonist at the N-methyl-D-aspartate receptor glycine site, was competitively reversed by glycine, by V3 and by BRU-C-34-A. When added with N-methyl-D-aspartate, V3 was three to four orders of magnitude more potent than glycine (EC50 values: about 20 pM and 150 nM, respectively) in enhancing [3H]noradrenaline release. Gp120 did not release glycine or serine from synaptosomes, thus excluding indirect actions through these agents. To conclude, gp120 may act following recognition by its V3 sequence of a high-affinity site possibly coincident with the glycine site of N-methyl-D-aspartate receptors present on hippocampal terminals of noradrenergic neurons. Considering the importance of N-methyl-D-aspartate receptor activation and of noradrenaline in cognitive processes, the effects of gp120 and V3 described here may be relevant to the pathology of AIDS dementia.