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 Ca 2+ transients via activation of a long-lived, store-operated Ca 2+ 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.
Original language | English (US) |
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Pages (from-to) | C998-C1008 |
Journal | American Journal of Physiology - Cell Physiology |
Volume | 286 |
Issue number | 5 55-5 |
DOIs | |
State | Published - May 2004 |
Keywords
- Barium
- Clotrimazole
- Nelfinavir
ASJC Scopus subject areas
- Physiology
- Cell Biology