Involvement of inositol 1,4,5-trisphosphate-regulated stores of intracellular calcium in calcium dysregulation and neuron cell death caused by HIV-1 protein Tat

N. J. Haughey, C. P. Holden, A. Nath, J. D. Geiger

Research output: Contribution to journalArticlepeer-review

160 Scopus citations

Abstract

HIV-1 infection commonly leads to neuronal cell death and a debilitating syndrome known as AIDS-related dementia complex. The HIV-1 protein Tat is neurotoxic, and because cell survival as affected by the intracellular calcium concentration ([Ca2+](i)), we determined mechanisms by which Tat increased [Ca2+](i) and the involvement of these mechanisms in Tat-induced neurotoxicity. Tat increased [Ca2+](i) dose-dependently in cultured human fetal neurons and astrocytes. In neurons, but not astrocytes, we observed biphasic increases of [Ca2+](i). Initial transient increases were larger in astrocytes than in neurons and in both cell types were significantly attenuated by antagonists of inositol 1,4,5-trisphosphate (IP3)-mediated intracellular calcium release [8-(diethylamino)octyl-3,4,5-trimethoxybenzoate HCl (TMB-8) and xestospongin], an inhibitor of receptor-G1 protein coupling (pertussis toxin), and a phospholipase C inhibitor (neomycin). Tat significantly increased levels of IP3 threefold. Secondary increases of neuronal [Ca2+](i) in neurons were delayed and progressive as a result of excessive calcium influx and were inhibited by the glutamate receptor antagonists ketamine, MK-801, (±)-2-amino-5-phosphonopentanoic acid, and 6,7-dinitroquinoxaline-2,3-dione. Secondary increases of [Ca2+](i) did not occur when initial increases of [Ca2+](i) were prevented with TMB-8, xestospongin, pertussis toxin, or neomycin, and these inhibitors as well as thapsigargin inhibited Tat-induced neurotoxicity. These results suggest that Tat, via pertussis toxin-sensitive phospholipase C activity, reduces calcium release from IP3-sensitive intracellular stores, which leads to glutamate receptor-mediated calcium influx, dysregulation of [Ca2+](i), and Tat- induced neurotoxicity.

Original languageEnglish (US)
Pages (from-to)1363-1374
Number of pages12
JournalJournal of Neurochemistry
Volume73
Issue number4
DOIs
StatePublished - 1999

Keywords

  • Glutamate receptors
  • Human immunodeficiency virus type-1
  • Human neurons and astrocytes
  • Inositol trisphosphate
  • Intracellular calcium
  • Tat

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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