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The Journal of Neuroscience, July 30, 2003, 23(17):6810-6818

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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

Marco Feligioni,¹ Luca Raiteri,¹ Roberto Pattarini,⁴ Massimo Grilli,¹ Santina Bruzzone,² Paolo Cavazzani,⁵ Maurizio Raiteri,^1,3 and Anna Pittaluga^1,3

¹Pharmacology and Toxicology Section, Department of Experimental Medicine, ²Biochemistry Section, Department of Experimental Medicine, and ³Center of Excellence for Biomedical Research, University of Genova, 16148 Genova, Italy, ⁴Division of Neurovirology, University of Manitoba, Manitoba, Canada R3T 2N2, and ⁵Division of Neurosurgery, Galliera Hospital, 16128 Genova, Italy

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.

Key words: HIV-1; Tat; acetylcholine release; human cerebrocortex; rat cerebrocortex; calcium; inositoltrisphosphate receptors; ryanodine receptors; mGlu receptor

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Received Feb. 24, 2003; revised May. 19, 2003; accepted May. 29, 2003.

This article has been cited by other articles:

				M. Raiteri Functional pharmacology in human brain. Pharmacol. Rev., June 1, 2006; 58(2): 162 - 193. [Abstract] [Full Text] [PDF]

				F. Longordo, M. Feligioni, G. Chiaramonte, P. F. Sbaffi, M. Raiteri, and A. Pittaluga The Human Immunodeficiency Virus-1 Protein Transactivator of Transcription Up-Regulates N-Methyl-D-aspartate Receptor Function by Acting at Metabotropic Glutamate Receptor 1 Receptors Coexisting on Human and Rat Brain Noradrenergic Neurones J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 1097 - 1105. [Abstract] [Full Text] [PDF]

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