Premium
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
Author(s) -
Haughey N. J.,
Holden C.P.,
Nath A.,
Geiger J.D.
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.0731363.x
Subject(s) - pertussis toxin , calcium in biology , phospholipase c , thapsigargin , calcium , biology , inositol trisphosphate , neurotoxicity , ryanodine receptor , intracellular , inositol , microbiology and biotechnology , glutamate receptor , g protein , receptor , chemistry , biochemistry , medicine , toxicity
: 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 is affected by the intracellular calcium concentration ([Ca 2+ ] i ), we determined mechanisms by which Tat increased [Ca 2+ ] i and the involvement of these mechanisms in Tat‐induced neurotoxicity. Tat increased [Ca 2+ ] i dose‐dependently in cultured human fetal neurons and astrocytes. In neurons, but not astrocytes, we observed biphasic increases of [Ca 2+ ] 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 (IP 3 )‐mediated intracellular calcium release [8‐(diethylamino)octyl‐3,4,5‐trimethoxybenzoate HCl (TMB‐8) and xestospongin], an inhibitor of receptor‐G i protein coupling (pertussis toxin), and a phospholipase C inhibitor (neomycin). Tat significantly increased levels of IP 3 threefold. Secondary increases of neuronal [Ca 2+ ] 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 [Ca 2+ ] i did not occur when initial increases of [Ca 2+ ] 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, induces calcium release from IP 3 ‐sensitive intracellular stores, which leads to glutamate receptor‐mediated calcium influx, dysregulation of [Ca 2+ ] i , and Tat‐induced neurotoxicity.