Lovastatin inhibits cAMP- and calcium-stimulated chloride secretion by T84 cells.
Isoprenylated proteins function in the processes of signal transduction and membrane vesicle trafficking. To investigate the role of isoprenylated proteins in secretagogue-stimulated epithelial ion transport, we studied the effects of lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on adenosine 3',5'-cyclic monophosphate (cAMP)- and Ca(2+)-stimulated Cl- secretion by monolayers of T84 colonic epithelial cells. Lovastatin reduces protein isoprenylation in many cell types. In T84 cells, lovastatin reversibly inhibits forskolin-stimulated equivalent short-circuit current (I(sc)eq) by 50% after 2 days of treatment. The concentration of lovastatin resulting in half-maximal effects on forskolin-stimulated I(sc)eq is consistent with inhibition of protein isoprenylation, and lovastatin effects on forskolin-stimulated I(sc)eq are not associated with inhibition of cholesterol or glycoprotein biosynthesis. Lovastatin blocks N6,2'-O-dibutyryladenosine 3',5'-cyclic monophosphate- and ionomycin-stimulated Isc, suggesting that it inhibits a process beyond the stimulation of cAMP and Ca2+ second-messenger systems. In monolayers in which the basolateral membrane has been permeabilized with nystatin, lovastatin inhibits cAMP activation of a diphenylamine-2-carboxylate-sensitive, apical membrane Cl- conductance. Our results are consistent with the hypothesis that an isoprenylated protein is involved in the regulation of a secretagogue-activated apical membrane Cl- conductance in T84 cells.
Department of Physiology and Cell Biology, University of Texas Medical School, Houston 77225.
T W
TW
Ecay
J D
JD
Valentich
D002118:Calcium / Q000494:pharmacology*; D002460:Cell Line; D002712:Chlorides / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D003106:Colon / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D000242:Cyclic AMP / Q000494:pharmacology*; D004553:Electric Conductivity; D004594:Electrophysiology / Q000379:methods; D006031:Glycosylation; D008148:Lovastatin / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism; D015290:Second Messenger Systems
D002712:Chlorides; D011506:Proteins; D005576:Colforsin; D002784:Cholesterol; D008148:Lovastatin; D000242:Cyclic AMP; D002118:Calcium