Diarrhea-associated HIV-1 APIs Potentiate Muscarinic Activation of Cl- Secretion by T84 Cells via Prolongation of Cytosolic Ca2+ Signaling

Am J Physiol Cell Physiol. 2004 May;286(5):C998-C1008. doi: 10.1152/ajpcell.00357.2003. Epub 2003 Dec 30.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Calcium Signaling / drug effects*
  • Carbachol / pharmacology
  • Cell Line
  • Cell Membrane / metabolism
  • Chlorides / metabolism
  • Cytosol / metabolism
  • Diarrhea / chemically induced*
  • Drug Synergism
  • Electric Conductivity
  • HIV Infections / drug therapy*
  • HIV Infections / enzymology
  • HIV-1*
  • Humans
  • Intestinal Mucosa / metabolism*
  • Intracellular Membranes / metabolism
  • Middle Aged
  • Muscarinic Agonists / pharmacology
  • Nelfinavir / adverse effects*
  • Protease Inhibitors / adverse effects*
  • Time Factors

Substances

  • Chlorides
  • Muscarinic Agonists
  • Protease Inhibitors
  • Carbachol
  • Aspartic Acid Endopeptidases
  • Nelfinavir