Ca2+ release-activated Ca2+ channel blockade as a potential tool in antipancreatitis therapy
| Autor: | Eloise Stapleton, Shuang Peng, Oleg Vsevolodovich Gerasimenko, Solomiia V. Bychkova, Julia Vladimirovna Gerasimenko, Pawel E. Ferdek, Oleksiy Gryshchenko, Malcolm Begg, Tania O.G. Hébert, Ole H. Petersen |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
medicine.medical_specialty
Thapsigargin Patch-Clamp Techniques ORAI1 Protein Pancreatitis Alcoholic Vasodilator Agents ORAI2 Protein Acinar Cells Membrane Potentials Fatty Acids Monounsaturated chemistry.chemical_compound Mice Internal medicine medicine Animals Channel blocker Patch clamp Calcium Signaling Pancreas Ion transporter Cells Cultured Cholecystokinin Multidisciplinary Ion Transport Voltage-dependent calcium channel Dose-Response Relationship Drug Chemistry Biological Sciences Trypsin Calcium Channel Blockers Acetylcholine Endocrinology Barium Benzamides Hepatocytes Pyrazoles Calcium Calcium Channels Ion Channel Gating medicine.drug |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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