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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Begg, Malcolm Gerasimenko, Julia V. Gryshchenko, Oleksiy Stapleton, Eloise Petersen, Ole H. Gerasimenko, Oleg V. Ferdek, Pawel E. Hébert, Tania O. G. Bychkova, Solomiia Peng, Shuang |
| Description | Author Affiliation: Gerasimenko JV ( Medical Research Council Group, Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3AX Wales, United Kingdom.); |
| Abstract | Alcohol-related acute pancreatitis can be mediated by a combination of alcohol and fatty acids (fatty acid ethyl esters) and is initiated by a sustained elevation of the $Ca^{2+}$ concentration inside pancreatic acinar cells $([Ca^{2+}]_{i}),$ due to excessive release of $Ca^{2+}$ stored inside the cells followed by $Ca^{2+}$ entry from the interstitial fluid. The sustained $[Ca^{2+}]_{i}$ elevation activates intracellular digestive proenzymes resulting in necrosis and inflammation. We tested the hypothesis that pharmacological blockade of store-operated or $Ca^{2+}$ release-activated $Ca^{2+}$ channels (CRAC) would prevent sustained elevation of $[Ca^{2+}]_{i}$ and therefore protease activation and necrosis. In isolated mouse pancreatic acinar cells, CRAC channels were activated by blocking $Ca^{2+}$ ATPase pumps in the endoplasmic reticulum with thapsigargin in the absence of external $Ca^{2+}.$ $Ca^{2+}$ entry then occurred upon admission of $Ca^{2+}$ to the extracellular solution. The CRAC channel blocker developed by GlaxoSmithKline, GSK-7975A, inhibited store-operated $Ca^{2+}$ entry in a concentration-dependent manner within the range of 1 to 50 μM $(IC_{50}$ = 3.4 μM), but had little or no effect on the physiological $Ca^{2+}$ spiking evoked by acetylcholine or cholecystokinin. Palmitoleic acid ethyl ester (100 μM), an important mediator of alcohol-related pancreatitis, evoked a sustained elevation of $[Ca^{2+}]_{i},$ which was markedly reduced by CRAC blockade. Importantly, the palmitoleic acid ethyl ester-induced trypsin and protease activity as well as necrosis were almost abolished by blocking CRAC channels. There is currently no specific treatment of pancreatitis, but our data show that pharmacological CRAC blockade is highly effective against toxic $[Ca^{2+}]_{i}$ elevation, necrosis, and trypsin/protease activity and therefore has potential to effectively treat pancreatitis. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 32 |
| Volume Number | 110 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2013-08-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Calcium Channel Blockers Pharmacology Calcium Channels Metabolism Calcium Ion Channel Gating Drug Effects Pancreatitis, Alcoholic Drug Therapy Acetylcholine Acinar Cells Cytology Animals Barium Benzamides Calcium Signaling Cells, Cultured Dose-Response Relationship, Drug Fatty Acids, Monounsaturated Hepatocytes Ion Transport Membrane Potentials Mice Pancreas Patch-Clamp Techniques Pyrazoles Vasodilator Agents Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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