Submitted on March 27, 2007
Accepted on June 9, 2007
Modulatory Role of Phosphoinositide 3-Kinase (PI3K) in Gastric Acid Secretion
Shelley E. Mettler1, Sara Ghayouri1, Gunjan P Christensen1, and John G. Forte1*
1 Molecular & Cell Biology, University of California, Berkeley, California, United States
* To whom correspondence should be addressed. E-mail: jforte{at}berkeley.edu.
The gastric parietal is responsible for the secretion of HCl into the lumen of the stomach mainly due to stimulation by histamine via the cAMP pathway. However, the participation of several other receptors and pathways have been discovered to influence both stimulation and inhibition of acid secretion (e.g. cholinergic). Here we examine the role of PI3K in the modulation of acid secretion. Treatment of isolated gastric glands and parietal cells with the PI3K inhibitor, LY294002 (LY), potentiated acid secretion in response to histamine to nearly the maximal secretion obtained with histamine plus phosphodiesterase inhibitors. As cAMP levels were elevated in response to histamine plus LY, but other means of elevating cAMP (e.g., forskolin, dbcAMP) were not influenced by LY, we posited that the effect might require activation of G-protein coupled histamine H2 receptors, possibly through the protein kinase B pathway (also known as Akt). Study of downstream effectors of PI3K showed that histaminergic stimulation increased Akt phosphorylation, which in turn was blocked by inhibition of PI3K. Expression studies showed that high expression of active Akt decreased acid secretion whereas dominant negative Akt increased acid secretion. Taken together, these data suggest stimulation with histamine increases the activity of PI3K leading to increased activity of Akt and decreased levels of cAMP in the parietal cell.
