Estradiol alters cholecystokinin stimulus-response coupling in rat pancreatic acini.
We have previously demonstrated that altered exocrine pancreatic stimulus-secretion coupling is associated with ovariectomy and chronic estradiol administration. To elucidate possible mechanisms underlying those effects we examined the ability of chronic administration of different doses of estradiol to regulate the CCK signal transduction pathway in isolated rat pancreatic acini. Doses of estradiol ranging from 0.5 to 119 micrograms/day were administered to ovariectomized rats for 18 days. Ovariectomy was associated with enhanced CCK-stimulated pancreatic amylase release, whereas estradiol dose dependently decreased the magnitude of CCK-stimulated amylase release. Ovariectomy was also associated with enhanced CCK receptor numbers on acinar cell membranes. Estradiol administration was associated with dose-dependent decreases in CCK receptor numbers. Neither ovariectomy nor estradiol administration affected CCK receptor affinity. Moreover, estradiol administration was associated with increased expression of the alpha-subunit of the heterotrimeric G protein Gq/11 (Galphaq/11). Recent findings (H. Ohnishi, S. A. Ernst, D. I. Yule, C. W. Baker, and J. A. Williams. J. Biol. Chem. 272: 16056-16061, 1997) demonstrate that Galphaq/11 may exert a tonic inhibitory effect on pancreatic enzyme release. In view of these findings, the increased expression of Galphaq/11 induced by estradiol likely contributes to the inhibition of pancreatic enzyme release. We conclude that the effect of estradiol to decrease pancreatic secretion is mediated through regulation of CCK receptor density and Galphaq/11 expression.
Blevins
G T
GT
Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
McCullough
S S
SS
Wilbert
T N
TN
Isom
R M
RM
Chowdhury
P
P
Miller
S T
ST
D000681:Amylases / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002766:Cholecystokinin / Q000494:pharmacology / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology* / Q000502:physiology; D005260:Female; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D010052:Ovariectomy; D010179:Pancreas / Q000187:drug effects / Q000502:physiology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000096:biosynthesis / Q000502:physiology*; D012844:Sincalide / Q000378:metabolism
D007457:Iodine Radioisotopes; D011949:Receptors, Cholecystokinin; D004958:Estradiol; D002766:Cholecystokinin; D000681:Amylases; D019204:GTP-Binding Proteins; D012844:Sincalide