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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Pancreatic protease activation by alcohol metabolite depends on Ca~(2+) release via acid store IP_3 receptors
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Pancreatic protease activation by alcohol metabolite depends on Ca~(2+) release via acid store IP_3 receptors

机译：酒精代谢产物对胰腺蛋白酶的活化取决于通过酸存储IP_3受体释放的Ca〜（2+）

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摘要

Toxic alcohol effects on pancreatic acinar cells, causing the often fatal human disease acute pancreatitis, are principally mediated by fatty acid ethyl esters (non-oxidative products of alcohol and fatty acids), emptying internal stores of Ca~(2+). This excessive Ca~(2+) liberation induces Ca~(2+)-dependent necrosis due to intracellular trypsin activation. Our aim was to identify the specific source of the Ca~(2+) release linked to the fatal intracellular protease activation. In 2-photon permeabilized mouse pancreatic acinar cells, we monitored changes in the Ca~(2+) concentration in the thapsigargin-sensitive endoplasmic reticulum (ER) as well as in a bafilomycin-sensitive acid compartment, localized exclusively in the apical granular pole. We also assessed trypsin activity in the apical granular region. Palmitoleic acid ethyl ester (POAEE) elicited Ca~(2+) release from both the ER as well as the acid pool, but trypsin activation depended predominantly on Ca~(2+) release from the acid pool, that was mainly mediated by functional inositol 1,4,5-trisphosphate receptors (IP3RS) of types 2 and 3. POAEE evoked very little Ca~(2+) release and trypsin activation when IP3RS of both types 2 and 3 were knocked out. Antibodies against IP3RS of types 2 and 3, but not type 1, markedly inhibited POAEE-elicited Ca~(2+) release and trypsin activation. We conclude that Ca~(2+) release through IP3RS of types 2 and 3 in the acid granular Ca~(2+) store induces intracellular protease activation, and propose that this is a critical process in the initiation of alcohol-related acute pancreatitis.
机译：有毒酒精对胰腺腺泡细胞的影响，通常是致命的人类急性胰腺炎，主要由脂肪酸乙酯（酒精和脂肪酸的非氧化产物）介导，清空Ca〜（2+）的内部储存。由于细胞内胰蛋白酶的活化，这种过量的Ca〜（2+）释放诱导Ca〜（2+）依赖性坏死。我们的目的是确定与致命的细胞内蛋白酶激活有关的Ca〜（2+）释放的具体来源。在2光子透化的小鼠胰腺腺泡细胞中，我们监测了毒胡萝卜素敏感的内质网（ER）以及巴氟霉素敏感的酸区室中Ca〜（2+）浓度的变化，该区室仅位于心尖颗粒极。我们还评估了顶端颗粒区域的胰蛋白酶活性。棕榈油酸乙酯（POAEE）引起ER和酸池中Ca〜（2+）的释放，但胰蛋白酶的活化主要取决于酸池中Ca〜（2+）的释放，这主要是由功能性介导的。 2型和3型肌醇1,4,5-三磷酸受体（IP3RS）当敲除2型和3型IP3RS时，POAEE几乎不会引起Ca〜（2+）释放和胰蛋白酶活化。针对2型和3型而非3型IP3RS的抗体显着抑制了POAEE引起的Ca〜（2+）释放和胰蛋白酶激活。我们得出结论，酸性颗粒状Ca〜（2+）存储区中通过2型和3型IP3RS释放的Ca〜（2+）诱导细胞内蛋白酶激活，并提出这是引发酒精相关性急性胰腺炎的关键过程。

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  • 作者

    Julia V. Gerasimenko; Gyoergy Lur; Mark W. Sherwood; Etsuko Ebisui; Alexei V. Tepikin; Katsuhiko Mikoshiba; Oieg V. Gerasimenko; Ole H. Petersen;

  • 作者单位

    Medical Research Council Group, Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Crown Street, Liverpool, L69 3BX, United Kingdom;

    Medical Research Council Group, Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Crown Street, Liverpool, L69 3BX, United Kingdom;

    Laboratory for Developmental Neurobiology, Riken Brain Science Institute, 2-1 Hirosawa, Wako City, Saitama, 351-0198 Japan;

    Laboratory for Developmental Neurobiology, Riken Brain Science Institute, 2-1 Hirosawa, Wako City, Saitama, 351-0198 Japan;

    Medical Research Council Group, Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Crown Street, Liverpool, L69 3BX, United Kingdom;

    Laboratory for Developmental Neurobiology, Riken Brain Science Institute, 2-1 Hirosawa, Wako City, Saitama, 351-0198 Japan;

    Medical Research Council Group, Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Crown Street, Liverpool, L69 3BX, United Kingdom;

    Medical Research Council Group, Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Crown Street, Liverpool, L69 3BX, United Kingdom;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    calcium; inositol trisphopshate receptors; pancreatitis;

    机译：钙;肌醇三磷酸受体;胰腺炎;

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