PT - JOURNAL ARTICLE AU - Fabio Longordo AU - Marco Feligioni AU - Greta Chiaramonte AU - Pier Filippo Sbaffi AU - Maurizio Raiteri AU - Anna Pittaluga TI - The Human Immunodeficiency Virus-1 Protein Transactivator of Transcription Up-Regulates <em>N</em>-Methyl-<span class="sc">d</span>-aspartate Receptor Function by Acting at Metabotropic Glutamate Receptor 1 Receptors Coexisting on Human and Rat Brain Noradrenergic Neurones AID - 10.1124/jpet.105.099630 DP - 2006 Jun 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 1097--1105 VI - 317 IP - 3 4099 - http://jpet.aspetjournals.org/content/317/3/1097.short 4100 - http://jpet.aspetjournals.org/content/317/3/1097.full SO - J Pharmacol Exp Ther2006 Jun 01; 317 AB - We investigated the effects of the human immunodeficiency virus-1 transactivator of transcription (Tat) on the release of norepinephrine (NE) from human and rat brain synaptosomes. Tat could not evoke directly release of [3H]NE. In the presence of Tat (1 nM), N-methyl-d-aspartate (NMDA) concentrations unable to release (human synaptosomes) or slightly releasing (rat synaptosomes) [3H]NE became very effective. The NMDA/Tat-evoked release depends on NMDA receptors (NMDARs) since it was abolished by MK-801 (dizocilpine). Tat binding at NMDARs was excluded. The NMDA-induced release of [3H]NE in the presence of glycine was further potentiated by Tat. The release evoked by NMDA/glycine/Tat depends on metabotropic glutamate receptor 1 (mGluR1) activation, since it was halved by mGluR1 antagonists. Tat seems to act at the glutamate recognition site of mGluR1. Recently, Tat was shown to release [3H]acetylcholine from human cholinergic terminals; here, we demonstrate that this effect is also mediated by presynaptic mGluR1. The peptide sequence Tat41–60, but not Tat61–80, mimicked Tat. Phospholipase C, protein kinase C, and cytosolic tyrosine kinase are involved in the NMDA/glycine/Tat-evoked [3H]NE release. To conclude, Tat can represent a potent pathological agonist at mGlu1 receptors able to release acetylcholine from human cholinergic terminals and up-regulate NMDARs mediating NE release from human and rat noradrenergic terminals. The American Society for Pharmacology and Experimental Therapeutics