title: The human immunodeficiency virus-1 protein Tat and its discrete fragments evoke selective release of acetylcholine from human and rat cerebrocortical terminals through species-specific mechanisms.
abstract: The effect of the human immunodeficiency virus-1 protein Tat was investigated on neurotransmitter release from human and rat cortical nerve endings. Tat failed to affect the release of several neurotransmitters, such as glutamate, GABA, norepinephrine, and others, but it evoked the release of [3H]ACh via increase of cytosolic [Ca2+]. In human nerve terminals, the Tat effect partly depends on Ca2+ entry through voltage-sensitive Ca2+ channels, because Cd2+ halved the Tat-evoked release. Activation of group I metabotropic glutamate receptors (mGluR) and mobilization of Ca2+ from IP3-sensitive intraterminal stores are also involved, because the Tat effect was prevented by mGluR antagonists 2-methyl-6-(phenylethynyl)pyridine hydrochloride and 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester and by the IP3 receptor antagonists heparin and xestospongin C. Furthermore, the group I selective mGlu agonist (RS)-3,5-dihydroxyphenylglycine enhanced [3H]ACh release. In rat nerve terminals, the Tat-evoked release neither depends on external Ca2+ ions entry nor on IP3-mediated mechanisms. Tat seems to cause mobilization of Ca2+ from ryanodine-sensitive internal stores because its effect was prevented by both 8-bromo-cyclic adenosine diphosphate-ribose and dantrolene. The Tat-evoked release from human synaptosomes was mimicked by the peptide sequences Tat 32-62, Tat 49-86, and Tat 41-60. In contrast, the Tat 49-86 and Tat 61-80 fragments, but not the Tat 32-62 fragment, were active in rat synaptosomes. In conclusion, Tat elicits Ca2+-dependent [3H]ACh release by species-specific intraterminal mechanisms by binding via discrete amino acid sequences to different receptive sites on human and rat cholinergic terminals.
authors.affiliation: Pharmacology and Toxicology Section, Department of Experimental Medicine, University of Genova, 16148 Genova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Feligioni
authors.forename: Luca
authors.initials: L
authors.lastname: Raiteri
authors.forename: Roberto
authors.initials: R
authors.lastname: Pattarini
authors.forename: Massimo
authors.initials: M
authors.lastname: Grilli
authors.forename: Santina
authors.initials: S
authors.lastname: Bruzzone
authors.forename: Paolo
authors.initials: P
authors.lastname: Cavazzani
authors.forename: Maurizio
authors.initials: M
authors.lastname: Raiteri
authors.forename: Anna
authors.initials: A
authors.lastname: Pittaluga
mesh_terms: D000109:Acetylcholine / Q000032:analysis / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels; D002540:Cerebral Cortex / Q000737:chemistry*; D002794:Choline / Q000378:metabolism; D036563:Cyclic ADP-Ribose / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D015696:Gene Products, tat / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008297:Male; D008875:Middle Aged; D018377:Neurotransmitter Agents / Q000032:analysis / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D017729:Presynaptic Terminals / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism; D013045:Species Specificity; D013574:Synaptosomes / Q000737:chemistry / Q000187:drug effects; D014316:Tritium; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D015220:Calcium Channels; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D015696:Gene Products, tat; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018377:Neurotransmitter Agents; D010446:Peptide Fragments; D018160:Receptors, Cytoplasmic and Nuclear; D017470:Receptors, Glutamate; D054322:tat Gene Products, Human Immunodeficiency Virus; D014316:Tritium; D036563:Cyclic ADP-Ribose; D015544:Inositol 1,4,5-Trisphosphate; D002794:Choline; D000109:Acetylcholine; D002118:Calcium