Novel Roles of AMPK in Gastrointestinal Ion Transport

BACKGROUND: The AMP-activated protein kinase (AMPK) is a ubiquitous multi-subunit protein that acts as an intracellular "energy sensor". In response to cellular stress factors, such as hypoxia, glucose deprivation and exercise, it adapts mostly metabolic pathways to prevent ATP depletion of the cell. However, AMPK has recently emerged as a potent modulator of ion transport in a variety of epithelia. The aim of this work is to elucidate the effects of AMPK on gastrointestinal ion transport mechanisms. In particular, three physiological and pathophysiological ion transport processes and their modulation by AMPK were investigated: 1. The influence of AMPK activation on H,K-ATPase mediated gastric acid secretion. 2. The role of AMPK as a modulator of intestinal chloride secretion during states of hypoxia. 3. The modulation of cholera-toxin induced intestinal chloride secretion by AMPK.;METHODS: Real-time fluorescent measurements of intracellular pH and chloride concentrations were used to study proton secretion of isolated gastric glands and chloride efflux from isolated colonic crypts. Furthermore, short circuit current was measured in intestinal sheets. AMPK was activated by treatment with the pharmacological agents AICAR or metformin and inhibited with compound C.;RESULTS: 1. Activation of AMPK significantly reduced proton extrusion by the gastric H,K-ATPase. 2. Hypoxia reduced intestinal chloride secretion. Chloride secretion could be reestablished by inhibition of AMPK. 3. Cholera-toxin stimulated intestinal chloride and water secretion could be inhibited by activation of AMPK.;CONCLUSION: AMPK is a potent regulator of gastrointestinal ion transport. In the gastric parietal cell, AMPK may serve as an off-switch for gastric acid secretion in the face of decreased intracellular energy levels. In the intestine, AMPK mediates the inhibitory effects of hypoxia on chloride secretion. Maintenance of chloride secretion during hypoxia may have beneficial effects on ischemic injury. Furthermore, pharmacological activation of AMPK can ameliorate deranged ion transport in the process of secretory diarrhea.