AMP-activated protein kinase: a physiological off switch for murine gastric acid secretion.
Adenosine monophosphate (AMP)-activated protein kinase (AMPK) has been shown to be a metabolic energy regulator in various cells. Activation is a direct result of rising AMP concentration coupled with falling adenosine triphosphate (ATP). AMPK activation during metabolic stress consequently reduces cellular ATP consumption. The gastric parietal cell has a large abundance of mitochondria per cell volume due to the numerous energy-dependent transporters and channels responsible for acid secretion. We identified AMPK in the parietal cell as a metabolic energy regulator that can switch acid secretion off as cellular ATP levels fall. AMPK presence in murine gastric glands was evaluated by immunofluorescent localization. We used a digital imaging system to monitor acid secretion as observed by proton efflux from parietal cells in hand-dissected gastric glands loaded with the pH-sensitive dye 2',7'-bis-(2-carboxyethyl)-5-(and 6)-carboxyfluorescein. Individual murine gastric glands were exposed to histamine, pentagastrin, or carbachol. AMPK was pharmacologically activated with 5-aminoimidazole-4-carboxamide-1-beta-D: -riboside (AICAR) monophosphate or inhibited with 6-[4-(2-piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyyrazolo[1,5-a] pyrimidine (compound C) or ATP. Acid secretion was evaluated under these conditions as the rate of intracellular pH recovery. In addition, whole-stomach pH measurements were performed. Immunofluorescent localization confirmed the presence of AMPK in gastric mucosa. Exposure to AICAR monophosphate significantly reduced secretagogue-induced acid secretion; addition of compound C or ATP restored acid secretion. Our results indicate that secretagogue-induced acid secretion could be significantly reduced with AMPK activation and restored with its deactivation. We therefore propose the AMPK as a cellular metabolic off switch for gastric acid secretion.
Sidani
Shafik
S
Department of Surgery, Yale University, 310 Cedar Street, New Haven, CT 06511, USA.
Kopic
Sascha
S
Socrates
Thenral
T
Kirchhoff
Philipp
P
Föller
Michael
M
Murek
Michael
M
Capasso
Anna
A
Geibel
John P
JP
D055372:AMP-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D005744:Gastric Acid / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008810:Mice, Inbred C57BL; D010295:Parietal Cells, Gastric / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*
D004791:Enzyme Inhibitors; D055372:AMP-Activated Protein Kinases