Human immunodeficiency virus type 1 Tat protein directly activates neuronal N-methyl-D-aspartate receptors at an allosteric zinc-sensitive site.

Abstract	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.
Authors	L Song, A Nath, J D Geiger, A Moore, S Hochman
Journal	Journal of neurovirology (J Neurovirol) Vol. 9 Issue 3 Pg. 399-403 (Jun 2003) ISSN: 1355-0284 [Print] United States
PMID	12775422 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References	Excitatory Amino Acid Antagonists Gene Products, tat NR1 NMDA receptor Receptors, N-Methyl-D-Aspartate tat Gene Products, Human Immunodeficiency Virus Ketamine 2-Amino-5-phosphonovalerate Kynurenic Acid Zinc 5,7-dichlorokynurenic acid
Topics	2-Amino-5-phosphonovalerate (pharmacology) Action Potentials Allosteric Regulation (drug effects) Allosteric Site (drug effects) Animals Excitatory Amino Acid Antagonists (pharmacology) Gene Products, tat (chemistry, pharmacology, physiology, toxicity) HIV-1 (physiology) Hippocampus (cytology) Humans Ketamine (pharmacology) Kynurenic Acid (analogs & derivatives, pharmacology) Neurons (physiology, virology) Patch-Clamp Techniques Protein Interaction Mapping Rats Rats, Sprague-Dawley Receptors, N-Methyl-D-Aspartate (agonists, antagonists & inhibitors, chemistry) Zinc (pharmacology) tat Gene Products, Human Immunodeficiency Virus

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