Activation of AMPK Inhibits Cholera Toxin Stimulated Chloride Secretion in Human and Murine Intestine

Autor: Danielle Collins, Nadia Hoekstra, Nadia A. Ameen, Desmond C. Winter, John P. Geibel, Anne Collaco, Lisa Huetter, Sascha Kopic, Ailín C. Rogers, Alan W. Baird
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Bacterial Diseases
Male
Anatomy and Physiology
Digestive Physiology
lcsh:Medicine
Cystic Fibrosis Transmembrane Conductance Regulator
AMP-Activated Protein Kinases
medicine.disease_cause
chemistry.chemical_compound
Mice
Cholera
Gastrointestinal Infections
Intestinal Mucosa
Phosphorylation
lcsh:Science
Multidisciplinary
Forskolin
biology
Cholera toxin
Cystic fibrosis transmembrane conductance regulator
Intestines
Infectious Diseases
Chloride channel
Medicine
Pediatric Gastroenterology
Research Article
medicine.medical_specialty
Cholera Toxin
Colon
Gastroenterology and Hepatology
In Vitro Techniques
Chlorides
Internal medicine
medicine
Animals
Humans
Secretion
Protein kinase A
Biology
lcsh:R
AMPK
Rats
Enzyme Activation
Endocrinology
chemistry
biology.protein
lcsh:Q
Secretagogue
Physiological Processes
Digestive System
Zdroj: PLoS ONE
PLoS ONE, Vol 8, Iss 7, p e69050 (2013)
ISSN: 1932-6203
Popis: Increased intestinal chloride secretion through chloride channels, such as the cystic fibrosis transmembrane conductance regulator (CFTR), is one of the major molecular mechanisms underlying enterotoxigenic diarrhea. It has been demonstrated in the past that the intracellular energy sensing kinase, the AMP-activated protein kinase (AMPK), can inhibit CFTR opening. We hypothesized that pharmacological activation of AMPK can abrogate the increased chloride flux through CFTR occurring during cholera toxin (CTX) mediated diarrhea. Chloride efflux was measured in isolated rat colonic crypts using real-time fluorescence imaging. AICAR and metformin were used to activate AMPK in the presence of the secretagogues CTX or forskolin (FSK). In order to substantiate our findings on the whole tissue level, short-circuit current (SCC) was monitored in human and murine colonic mucosa using Ussing chambers. Furthermore, fluid accumulation was measured in excised intestinal loops. CTX and forskolin (FSK) significantly increased chloride efflux in isolated colonic crypts. The increase in chloride efflux could be offset by using the AMPK activators AICAR and metformin. In human and mouse mucosal sheets, CTX and FSK increased SCC. AICAR and metformin inhibited the secretagogue induced rise in SCC, thereby confirming the findings made in isolated crypts. Moreover, AICAR decreased CTX stimulated fluid accumulation in excised intestinal segments. The present study suggests that pharmacological activation of AMPK effectively reduces CTX mediated increases in intestinal chloride secretion, which is a key factor for intestinal water accumulation. AMPK activators may therefore represent a supplemental treatment strategy for acute diarrheal illness.
Databáze: OpenAIRE
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