Diarrhea-associated HIV-1 APIs potentiate muscarinic activation of Cl- secretion by T84 cells via prolongation of cytosolic Ca2+ signaling.
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.
Rufo
Paul A
PA
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
Lin
Patricia W
PW
Andrade
Adriana
A
Jiang
Lianwei
L
Rameh
Lucia
L
Flexner
Charles
C
Alper
Seth L
SL
Lencer
Wayne I
WI
D000328:Adult; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D020013:Calcium Signaling / Q000187:drug effects*; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced*; D004357:Drug Synergism; D004553:Electric Conductivity; D015658:HIV Infections / Q000188:drug therapy* / Q000201:enzymology; D015497:HIV-1; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007425:Intracellular Membranes / Q000378:metabolism; D008875:Middle Aged; D018721:Muscarinic Agonists / Q000494:pharmacology; D019888:Nelfinavir / Q000009:adverse effects*; D011480:Protease Inhibitors / Q000009:adverse effects*; D013997:Time Factors
D002712:Chlorides; D018721:Muscarinic Agonists; D011480:Protease Inhibitors; D002217:Carbachol; D016282:Aspartic Acid Endopeptidases; D019888:Nelfinavir