The HIV-1 coat protein gp120 and some of its fragments potently activate native cerebral NMDA receptors mediating neuropeptide release

The objective of this study was to investigate the effects of the HIV-1 env elope protein gp120 and its peptide fragments on the function of N-methyl-d -aspartate (NMDA) receptors mediating release of cholecystokinin (CCK) and somatostatin (SRIF). These are nonconventional NMDA receptors recently foun d to be activated by glycine or d-serine 'only'. The release of cholecystok inin-like immunoreactivity (CCK-LI) and of somatostatin-like immunoreactivi ty (SRIF-LI) elicited by 12 mm K+ from superfused rat neocortex synaptosome s was potently increased by gp120, its cyclic V3 loop and the linear V3 seq uence BRU-C-34-A, but not by RP-135 (a central portion of BRU-C-34-A). The EC50 values of gp120 were 0.02 nm (CCK-LI release) and 0.01 nm (SRIF-LI rel ease). The releasing effect of gp120 was prevented by blocking the glycine site or the ion channel of NMDA receptors, but not the glutamate recognitio n site; in addition, the gp120 effect was strongly inhibited by nanomolar c oncentrations of Zn2+ ions and by low micromolar concentrations of ifenprod il. It is concluded that gp120 acts as a very potent agonist at the glycine site of NMDA receptors sited on CCK- and SRIF-releasing nerve endings; the protein is able to activate the receptor channel in the absence of glutama te. Gp120 activates the receptors through its V3 loop as peptide fragments related to V3 retain near-maximal activity. The sensitivity of the gp120 ef fect to both Zn2+ and ifenprodil would not be incompatible with the idea th at these NMDA receptors contain the triple subunit combination NR1/NR2A/NR2 B.