Diarrhea-associated HIV-1 APIs potentiate muscarinic activation of Cl- secretion by T84 cells via prolongation of cytosolic Ca2+ signaling |
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Authors: | Rufo Paul A Lin Patricia W Andrade Adriana Jiang Lianwei Rameh Lucia Flexner Charles Alper Seth L Lencer Wayne I |
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Affiliation: | GI Cell Biology, Combined Program in Pediatric Gastroenterology and Nutrition, Children's Hospital, 300 Longwood Ave., Boston, MA 02115, USA. wayne.lencer@childrens.harvard.edu |
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Abstract: | Aspartyl protease inhibitors (APIs) effectively extend the length and quality of life in human immunodeficiency virus (HIV)-infected patients, but dose-limiting side effects such as lipodystrophy, insulin resistance, and diarrhea have limited their clinical utility. Here, we show that the API nelfinavir induces a secretory form of diarrhea in HIV-infected patients. In vitro studies demonstrate that nelfinavir potentiates muscarinic stimulation of Cl- secretion by T84 human intestinal cell monolayers through amplification and prolongation of an apical membrane Ca2+-dependent Cl- conductance. This stimulated ion secretion is associated with increased magnitude and duration of muscarinically induced intracellular Ca2+ transients via activation of a long-lived, store-operated Ca2+ entry pathway. The enhanced intracellular Ca2+ signal is associated with uncoupling of the Cl- conductance from downregulatory intracellular mediators generated normally by muscarinic activation. These data show that APIs modulate Ca2+ signaling in secretory epithelial cells and identify a novel target for treatment of clinically important API side effects. nelfinavir; clotrimazole; barium |
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