Kongsuphol, Patthara and Cassidy, Diane and Romeiras, Francisco and Schreiber, Rainer and Mehta, Anil and Kunzelmann, Karl (2010) Metformin Treatment of Diabetes Mellitus Increases the Risk for Pancreatitis in Patients Bearing the CFTR-mutation S573C. CELLULAR PHYSIOLOGY AND BIOCHEMISTRY, 25 (4-5). pp. 389-396. ISSN 1015-8987, 1421-9778
Full text not available from this repository. (Request a copy)Abstract
Metformin use in diabetes can cause acidosis and might be linked to pancreatitis. Here, we mechanistically focus on this relationship via a point mutation in the cystic fibrosis transmembrane conductance regulator (CFTR; ABCC7). CFTR is an ATP-hydrolyzing, cAMP/PKA-activated anion channel regulating pancreatic bicarbonate/chloride secretion across duct-facing apical membranes in epithelia. CFTR has two nucleotide binding domains (NBD1/2) which clamp two ATP molecules across their opposed, inverted interfacial surfaces which generates anion-conductance after ATP hydrolysis. Notably, CFTR mutations not causal for classical cystic fibrosis segregate with unexplained pancreatitis and one of these lies in NBD1 near its ATP-clamp (S573C; close to the Walker B aspartate D572). We recently showed that after raising [cAMP], wt-CFTR chloride-conductance, when expressed in Xenopus oocytes, remains elevated despite the presence of metformin. Yet here, we find that S573C-CFTR manifests a metformin-inhibitable whole cell chloride-conductance after cAMP elevation. In the absence of metformin, cAMP-activated S573C-CFTR also displays a reduced anion-conductance relative to wt-CFTR. Furthermore, intra-oocyte acidification inhibited wt-CFTR and abolished S573C-CFTR conductance. We conclude that defective S573C-CFTR remains both poorly conducting and inhibited by metformin and intracellular acidosis. This might explain the propensity to pancreatitis with this rare CF mutation. Copyright (C) 2010 S. Karger AG, Basel
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ACTIVATED PROTEIN-KINASE; CYSTIC-FIBROSIS GENE; TRANSMEMBRANE CONDUCTANCE REGULATOR; HCO3-SECRETION; RENAL-FAILURE; BICARBONATE; CELLS; INHIBITION; TRANSPORT; Cystic fibrosis transmembrane conductance regulator; CFTR AMP; PKA AMP-activated protein kinase; S573C; Pancreatitis; Metformin; Pancreas; Chloride secretion |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Karl Kunzelmann |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 12 Aug 2020 09:06 |
| Last Modified: | 12 Aug 2020 09:06 |
| URI: | https://pred.uni-regensburg.de/id/eprint/25383 |
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