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Ca2+ release-activated Ca2+ channel blockade as a potential tool in antipancreatitis therapy

Gerasimenko, Julia Vladimirovna, Gryshchenko, Oleksiy, Ferdek, Pawel, Stapleton, Eloise, Hébert, Tania O.G., Bychkova, Solomiia, Peng, Shuang, Begg, Malcolm, Gerasimenko, Oleg Vsevolodovich and Petersen, Ole Holger 2013. Ca2+ release-activated Ca2+ channel blockade as a potential tool in antipancreatitis therapy. Proceedings of the National Academy of Sciences of the United States of America 110 (32) , pp. 13186-13191. 10.1073/pnas.1300910110

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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 Ca2+ concentration inside pancreatic acinar cells ([Ca2+]i), due to excessive release of Ca2+ stored inside the cells followed by Ca2+ entry from the interstitial fluid. The sustained [Ca2+]i elevation activates intracellular digestive proenzymes resulting in necrosis and inflammation. We tested the hypothesis that pharmacological blockade of store-operated or Ca2+ release-activated Ca2+ channels (CRAC) would prevent sustained elevation of [Ca2+]i and therefore protease activation and necrosis. In isolated mouse pancreatic acinar cells, CRAC channels were activated by blocking Ca2+ ATPase pumps in the endoplasmic reticulum with thapsigargin in the absence of external Ca2+. Ca2+ entry then occurred upon admission of Ca2+ to the extracellular solution. The CRAC channel blocker developed by GlaxoSmithKline, GSK-7975A, inhibited store-operated Ca2+ entry in a concentration-dependent manner within the range of 1 to 50 μM (IC50 = 3.4 μM), but had little or no effect on the physiological Ca2+ spiking evoked by acetylcholine or cholecystokinin. Palmitoleic acid ethyl ester (100 μM), an important mediator of alcohol-related pancreatitis, evoked a sustained elevation of [Ca2+]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 [Ca2+]i elevation, necrosis, and trypsin/protease activity and therefore has potential to effectively treat pancreatitis.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QH Natural history > QH301 Biology
Q Science > QP Physiology
Uncontrolled Keywords: capacitative Ca2+ entry; alcohol metabolite; pancreas; hepatocyte Ca2+ entry; AR42J
Publisher: National Academy of Sciences
ISSN: 0027-8424
Funders: MRC
Last Modified: 13 Jun 2019 02:08
URI: http://orca.cf.ac.uk/id/eprint/49488

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