Synergistic effects of HIV coat protein and NMDA receptor-mediated neurotoxicity.
Exposure of rat retinal cultures to HIV-1 coat protein gp120 for several minutes increases [Ca2+]i in approximately half of the ganglion cells; this effect is associated with delayed-onset neuronal injury, similar to that previously reported in NMDA receptor-mediated neurotoxicity. Here we show that NMDA antagonists can prevent both the rise in [Ca2+]i and subsequent neuronal damage engendered by 20 pM gp120. However, whole-cell patch-clamp recordings demonstrate that gp120 does not directly evoke an NMDA-like response or enhance glutamate/NMDA-activated currents. Moreover, complete protection from gp120-induced [Ca2+]i increases and neurotoxicity is afforded by incubation with glutamate-pyruvate transaminase, which breaks down endogenous glutamate as verified by HPLC. Since, under standard conditions in these cultures, neither glutamate nor a low picomolar concentration of gp120 is deleterious on its own, our results suggest that their neurotoxicity is synergistic.
Lipton
S A
SA
Department of Neurology Children's Hospital, Boston, Massachusetts.
Sucher
N J
NJ
Kaiser
P K
PK
Dreyer
E B
EB
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000410:Alanine Transaminase / Q000493:pharmacokinetics; D000818:Animals; D002118:Calcium / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D009498:Neurotoxins / Q000494:pharmacology*; D009994:Osmolar Concentration; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000378:metabolism
D005971:Glutamates; D015699:HIV Envelope Protein gp120; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D000410:Alanine Transaminase; D002118:Calcium