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 language | English (US) |
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Pages (from-to) | 1363-1374 |
Number of pages | 12 |
Journal | Journal of Neurochemistry |
Volume | 73 |
Issue number | 4 |
DOIs | |
State | Published - 1999 |
Externally published | Yes |
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