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 envelope 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 found to be activated by glycine or D-serine 'only'. The release of cholecystokinin-like immunoreactivity (CCK-LI) and of somatostatin-like immunoreactivity (SRIF-LI) elicited by 12 mM K+ from superfused rat neocortex synaptosomes was potently increased by gp120, its cyclic V3 loop and the linear V3 sequence 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 release). The releasing effect of gp120 was prevented by blocking the glycine site or the ion channel of NMDA receptors, but not the glutamate recognition site; in addition, the gp120 effect was strongly inhibited by nanomolar concentrations of Zn2+ ions and by low micromolar concentrations of ifenprodil. 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 glutamate. Gp120 activates the receptors through its V3 loop as peptide fragments related to V3 retain near-maximal activity. The sensitivity of the gp120 effect to both Zn2+ and ifenprodil would not be incompatible with the idea that these NMDA receptors contain the triple subunit combination NR1/NR2A/NR2B.
Gemignani
A
A
Department of Experimental Medicine, Pharmacology and Toxicology Section, Viale Cembrano 4, 16148 Genova, Italy.
Paudice
P
P
Pittaluga
A
A
Raiteri
M
M
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism* / Q000821:virology; D002766:Cholecystokinin / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000378:metabolism*; D015497:HIV-1; D007211:Indoles / Q000494:pharmacology; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism / Q000821:virology; D019335:Nitroarginine / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism; D010875:Pipecolic Acids / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013004:Somatostatin / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013574:Synaptosomes / Q000378:metabolism; D015032:Zinc / Q000494:pharmacology
D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D015699:HIV Envelope Protein gp120; D007211:Indoles; D008301:Maleimides; D010446:Peptide Fragments; D010875:Pipecolic Acids; D010879:Piperazines; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C084485:7-chlorothiokynurenic acid; D019335:Nitroarginine; C053672:selfotel; D013004:Somatostatin; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D002766:Cholecystokinin; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D007736:Kynurenic Acid; D015032:Zinc; C070515:bisindolylmaleimide I; C010739:ifenprodil; D011188:Potassium