Human brain N-methyl-D-aspartate receptors regulating noradrenaline release are positively modulated by HIV-1 coat protein gp120.
OBJECTIVE
To investigate the effect of HIV-1 gp120 on the function of glutamate receptors of the N-methyl-D-aspartate (NMDA) type in the human brain.


METHODS
The monitoring of neurotransmitter release from superfused isolated nerve endings is widely recognized as a technique appropriate for the study of neurotransmitter release and to attribute a precise localization to the site(s) of action of drugs able to modulate release.


METHODS
Synaptosomes (pinched-off nerve endings) were prepared from fresh human brain tissue samples removed during neurosurgery, labelled with [3H]-noradrenaline and superfused at a rate of 0.5 ml/min with NMDA in the presence of gp41, gp160, gp120 or the V3 loop, with or without NMDA receptor antagonists. Fractions of superfusate were collected and measured for radioactivity.


RESULTS
NMDA elicited a glycine-sensitive release of [3H]-noradrenaline from human brain synaptosomes. HIV-1 gp120 potentiated the NMDA (1 mM)-evoked [3H]-noradrenaline release (maximal effect approximately 110% at 1 nM). The release elicited by NMDA plus gp120 was prevented by the classical NMDA receptor antagonists dizocilpine or 7-chlorokynurenic acid, as well as by memantine. The potentiation by gp120 of the NMDA-evoked [3H]-noradrenaline release was mimicked by gp160 but not by gp41. The effect of gp120 was retained by the V3 loop. Finally, gp120 reversed (1 nM) and surmounted (10nM) the antagonism by 10 microM 7-chlorokynurenate of the NMDA-evoked [3H]-noradrenaline release.


CONCLUSIONS
gp 120 binds directly through the V3 loop at noradrenergic axon terminals in human brain neocortex and may alter the function of presynaptic NMDA receptors mediating regulation of noradrenaline release.
Pittaluga
A
A
Istituto di Farmacologia e Farmacognosia, University of Genoa, Italy.
Pattarini
R
R
Severi
P
P
Raiteri
M
M
D000328:Adult; D000368:Aged; D000495:Allosteric Site; D002540:Cerebral Cortex / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D015686:Gene Products, env / Q000494:pharmacology; D005998:Glycine / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology* / Q000502:physiology; D015497:HIV-1; D006801:Humans; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D016202:N-Methylaspartate / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology / Q000502:physiology; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D013574:Synaptosomes / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D015686:Gene Products, env; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D007736:Kynurenic Acid; C057013:7-chlorokynurenic acid; D005998:Glycine; D009638:Norepinephrine