title: The HIV-1 viral protein Tat increases glutamate and decreases GABA exocytosis from human and mouse neocortical nerve endings.
abstract: Human immunodeficiency virus-1 (HIV-1)-encoded transactivator of transcription (Tat) potentiated the depolarization-evoked exocytosis of [(3)H]D-aspartate ([(3)H]D-ASP) from human neocortical terminals. The metabotropic glutamate (mGlu) 1 receptor antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) prevented this effect, whereas the mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl) pyridine hydrochloride (MPEP) was ineffective. Western blot analysis showed that human neocortex synaptosomes possess mGlu1 and mGlu5 receptors. Tat potentiated the K(+)-evoked release of [(3)H]D-ASP or of endogenous glutamate from mouse neocortical synaptosomes in a CPCCOEt-sensitive and MPEP-insensitive manner. Deletion of mGlu1 receptors (crv4/crv4 mice) or mGlu5 receptors (mGlu5(-/-)mouse) silenced Tat effects. Tat enhanced inositol 1,4,5-trisphosphate production in human and mouse neocortical synaptosomes, consistent with the involvement of group I mGlu receptors. Tat inhibited the K(+)-evoked release of [(3)H]gamma-aminobutyric acid ([(3)H]GABA) from human synaptosomes and that of endogenous GABA or [(3)H]GABA from mouse nerve terminals; the inhibition was insensitive to CPCCOEt or MPEP. Tat-induced effects were retained by Tat(37-72) but not by Tat(48-85). In mouse neocortical slices, Tat facilitated the K(+)- and the veratridine-induced release of [(3)H]D-ASP in a CPCCOEt-sensitive manner and was ineffective in crv4/crv4 mouse slices. These observations are relevant to the comprehension of the pathophysiological effects of Tat in central nervous system and may suggest new potential therapeutic approaches to the cure of HIV-1-associated dementia.
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology and Toxicology, University of Genoa, 16148 Genoa, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Musante
authors.forename: Maria
authors.initials: M
authors.lastname: Summa
authors.forename: Elisa
authors.initials: E
authors.lastname: Neri
authors.forename: Aldamaria
authors.initials: A
authors.lastname: Puliti
authors.forename: Tomasz T
authors.initials: TT
authors.lastname: Godowicz
authors.forename: Paolo
authors.initials: P
authors.lastname: Severi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Battaglia
authors.forename: Maurizio
authors.initials: M
authors.lastname: Raiteri
authors.forename: Anna
authors.initials: A
authors.lastname: Pittaluga
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015536:Down-Regulation / Q000502:physiology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005089:Exocytosis / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D019579:Neocortex / Q000166:cytology / Q000378:metabolism*; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000494:pharmacology; D011188:Potassium / Q000633:toxicity; D017729:Presynaptic Terminals / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013574:Synaptosomes / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology*; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000502:physiology*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D010446:Peptide Fragments; D054322:tat Gene Products, Human Immunodeficiency Virus; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D011188:Potassium