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
: 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 ([Ca2+]i), we determined mechanisms by which Tat increased...
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Veröffentlicht in: | Journal of neurochemistry 1999-10, Vol.73 (4), p.1363-1374 |
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Zusammenfassung: | : 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 ([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‐Gi 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, induces calcium release
from IP3‐sensitive intracellular stores, which leads to glutamate
receptor‐mediated calcium influx, dysregulation of
[Ca2+]i, and Tat‐induced neurotoxicity. |
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ISSN: | 0022-3042 1471-4159 |
DOI: | 10.1046/j.1471-4159.1999.0731363.x |