Human immunodeficiency virus type 1 Tat protein directly activates neuronal N-methyl-D-aspartate receptors at an allosteric zinc-sensitive site.
The human immunodeficiency virus type 1 (HIV-1) regulatory protein Tat is neurotoxic and may be involved in the neuropathogenesis of HIV-1 dementia, in part via N-methyl-D-aspartate (NMDA) receptor activation. Here, in acutely isolated rat hippocampal neurons, Tat evoked inward currents reversing near 0 mV, with a negative slope conductance region characteristic of NMDA receptor activation. Although the NMDA receptor antagonist ketamine blocked Tat's actions, competitive glutamate- and glycine-binding site antagonists were ineffective (AP-5 and 5,7-dichlorokynurenate, respectively). Evidence for Tat acting at a distinct modulatory site on the NR1 subunit of NMDA receptors was provided by findings that 1 microM Zn(2+) abolished Tat-evoked responses in all neurons tested. Thus, Tat appears to excite neurons via direct activation of the NMDA receptor at an allosteric Zn(2+)-sensitive site.
Song
L
L
Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada.
Nath
A
A
Geiger
J D
JD
Moore
A
A
Hochman
S
S
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000200:Action Potentials; D000494:Allosteric Regulation / Q000187:drug effects; D000495:Allosteric Site / Q000187:drug effects*; D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D015696:Gene Products, tat / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology / Q000633:toxicity; D015497:HIV-1 / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007649:Ketamine / Q000494:pharmacology; D007736:Kynurenic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D009474:Neurons / Q000502:physiology / Q000821:virology*; D018408:Patch-Clamp Techniques; D025941:Protein Interaction Mapping; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000737:chemistry; D015032:Zinc / Q000494:pharmacology*; D054322:tat Gene Products, Human Immunodeficiency Virus
D018691:Excitatory Amino Acid Antagonists; D015696:Gene Products, tat; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D054322:tat Gene Products, Human Immunodeficiency Virus; D007649:Ketamine; D015763:2-Amino-5-phosphonovalerate; D007736:Kynurenic Acid; D015032:Zinc; C066192:5,7-dichlorokynurenic acid