{'fraction_non_alphanumeric': 0.05466735430634347, 'fraction_numerical': 0.018050541516245487, 'mean_word_length': 6.66798418972332, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
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

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 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.