Diarrhea-associated HIV-1 APIs potentiate muscarinic activation of Cl- secretion by T84 cells via prolongation of cytosolic Ca2+ signaling.

Rufo PA, Lin PW, Andrade A, Jiang L, Rameh L, Flexner C, Alper SL, Lencer WI
Am J Physiol Cell Physiol. 2004 286 (5): C998-C1008

PMID: 15075198 · DOI:10.1152/ajpcell.00357.2003

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 Ca(2+)-dependent Cl(-) conductance. This stimulated ion secretion is associated with increased magnitude and duration of muscarinically induced intracellular Ca(2+) transients via activation of a long-lived, store-operated Ca(2+) entry pathway. The enhanced intracellular Ca(2+) signal is associated with uncoupling of the Cl(-) conductance from downregulatory intracellular mediators generated normally by muscarinic activation. These data show that APIs modulate Ca(2+) signaling in secretory epithelial cells and identify a novel target for treatment of clinically important API side effects.

MeSH Terms (21)

Adult Aspartic Acid Endopeptidases Calcium Signaling Carbachol Cell Line Cell Membrane Chlorides Cytosol Diarrhea Drug Synergism Electric Conductivity HIV-1 HIV Infections Humans Intestinal Mucosa Intracellular Membranes Middle Aged Muscarinic Agonists Nelfinavir Protease Inhibitors Time Factors

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