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AMP-activated Protein Kinase: A Physiological Off Switch for Gastric Acid Secretion
Shafik M Sidani, Thenral Socrates, Michael Foller, Walter E Longo, John P Geibel
Yale University, New Haven, CT
Backround: AMP-activated protein kinase (AMPK) has been shown to be a metabolic sensor and regulator of energy balance in various mammalian cells. Activation follows rising AMP coupled with falling ATP resulting in a reduction in ATP-consuming processes. The gastric parietal cell is known to have a particular abundance of mitochondria considering the numerous energy dependent transporters and channels responsible for acid secretion. In that light, we elected to localize AMPK in the parietal cell as a metabolic fuel sensor and regulator that can switch acid secretion off as cellular ATP levels fall.
Methods: AMPK presence was evaluated by Western blot analysis of lysate protein obtained from gastric mucosa of murine corpus as well as by immunohistochemical localization.
We used a digital-imaging system to observe proton efflux from parietal cells in hand dissected gastric glands loaded with the pH sensitive dye BCECF. Individual murine gastric glands were exposed to either: histamine (100μmol), pentagastrin (100 μmol), or carbachol (100μmol) and a HCO3-/Na+ free perfusate to induce an acid load. To activate AMPK we used 10mM AICAR. Subsequently, AMPK was deactivated using 20µM Compound C or 5mM ATP in streptolysin-O-permeabilized glands. Acid secretion was measured as intracellular pH recovery rates.
Isolated perfused whole stomach pH measurements were also done.
Results: Western blot analysis and immunohistochemical localization demonstrated the presence of AMPK in the parietal cell. AICAR significantly reduced secretagogue-induced acid secretion whereas Compound C and ATP restored it.
Conclusion: We demonstrate the presence of AMPK and a regulatory role for it in the gastric parietal cell as a physiological off switch for acid secretion.
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