Inhibition of CN (protein phosphatase-2B) suppresses Ca2+-mediated acid secretion in rats.
OBJECTIVE
It has been suggested that CN (calcineurin, protein phosphatase-2B) regulates signal transduction, particularly in various secretory cells. In this study, we examined whether CN plays a role in stimulus-secretion coupling of gastric parietal cells.


METHODS
Localization of CN in gastric epithelial cells was examined immunohistochemically. The role of CN in the acid secretion pathway of gastric parietal cells was assessed by evaluating the effect of FK506, a specific inhibitor of CN, on gastric acid secretion in pylorus-ligated rats. In addition, the effect of FK506 on secretagogue (carbachol, tetragastrin and histamine)-stimulated acid secretion was investigated in lumen-perfused rats.


RESULTS
CN was specifically expressed in gastric parietal cells and chief cells of the gastric mucosal epithelium immunohistochemically. FK506 dose-dependently inhibited gastric acid secretion in pylorus-ligated rats. In lumen-perfused rats, FK506 completely inhibited acid secretion prestimulated by carbachol and tetragastrin, agonists known to increase cytosolic Ca2+, but did not affect acid secretion prestimulated by histamine.


CONCLUSIONS
Our findings demonstrate that FK506 has a potent antisecretory effect in parietal cells through inhibition of only Ca2+-mediated acid secretion pathways. As FK506 is known to specifically inhibit CN, which plays an important role in signal transduction in various secretory cells, protein dephosphorylation signalling might also be crucial for gastrin and M3 muscarine receptor-mediated stimulation of proton pump.
Itoh
S
S
Department of Internal Medicine, Akita University School of Medicine, Japan.
Otaka
M
M
Odashima
M
M
Zeniya
A
A
Okuyama
A
A
Jin
M
M
Otani
S
S
Iwabuchi
A
A
Sasahara
H
H
Masamune
O
O
Watanabe
S
S
D000818:Animals; D019703:Calcineurin / Q000502:physiology; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000378:metabolism*; D003864:Depression, Chemical; D005744:Gastric Acid / Q000378:metabolism*; D005745:Gastric Acidity Determination; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D016559:Tacrolimus / Q000494:pharmacology
D065095:Calcineurin Inhibitors; D019703:Calcineurin; D002118:Calcium; D016559:Tacrolimus