Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca2+ release through IP3 receptors
Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca2+ release through IP3 receptors
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DOI：
10.1073/pnas.1016534108
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发表时间：
2011-04-05
影响因子：
11.1
通讯作者：
Gerasimenko, Oleg V.
中科院分区：
文献类型：
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作者：
Gerasimenko, Julia V.;Lur, Gyorgy;Gerasimenko, Oleg V.
酒精滥用是一个重大的全球健康问题，但其行动机制仍有许多不确定性。迄今为止，乙醇对质膜离子通道的影响是最受关注的。我们现在研究了对胰腺腺泡细胞内钙通道的作用。我们的目的是发现酒精影响钙稳态的机制，从而了解酒精如何触发细胞内胰蛋白酶原的过早激活，这是酒精性胰腺炎的起始步骤。我们使用从野生型小鼠或敲除2型或2型和3型肌醇三磷酸受体的小鼠中分离的完整或双光子渗透的腺泡细胞。在渗透化的胰腺腺泡细胞中，即使相对较低的乙醇浓度也会引起细胞内储存的钙释放和细胞内胰蛋白酶原活化。钙传感器钙调素（在正常的细胞内浓度）显著降低乙醇诱导的钙释放和胰蛋白酶原激活，这种作用被钙调素抑制剂肽阻止。钙调素激活剂实际上消除了乙醇对完整细胞的适度影响。在2型肌醇三磷酸受体敲除小鼠的细胞中，乙醇诱导的钙释放和胰蛋白酶原激活均显著降低。在双肌醇三磷酸受体（2型和3型）敲除小鼠的细胞中观察到更深刻的减少。肌醇三磷酸受体，正常胰腺刺激-分泌偶联所必需的，也负责毒性乙醇作用。钙调素通过降低钙释放敏感性来起到保护作用。
Alcohol abuse is a major global health problem, but there is still much uncertainty about the mechanisms of action. So far, the effects of ethanol on ion channels in the plasma membrane have received the most attention. We have now investigated actions on intracellular calcium channels in pancreatic acinar cells. Our aim was to discover the mechanism by which alcohol influences calcium homeostasis and thereby understand how alcohol can trigger premature intracellular trypsinogen activation, which is the initiating step for alcohol-induced pancreatitis. We used intact or two-photon permeabilized acinar cells isolated from wild-type mice or mice in which inositol trisphosphate receptors of type 2 or types 2 and 3 were knocked out. In permeabilized pancreatic acinar cells even a relatively low ethanol concentration elicited calcium release from intracellular stores and intracellular trypsinogen activation. The calcium sensor calmodulin (at a normal intracellular concentration) markedly reduced ethanol-induced calcium release and trypsinogen activation in permeabilized cells, effects prevented by the calmodulin inhibitor peptide. A calmodulin activator virtually abolished the modest ethanol effects in intact cells. Both ethanol-elicited calcium liberation and trypsinogen activation were significantly reduced in cells from type 2 inositol trisphosphate receptor knockout mice. More profound reductions were seen in cells from double inositol trisphosphate receptor (types 2 and 3) knockout mice. The inositol trisphosphate receptors, required for normal pancreatic stimulus-secretion coupling, are also responsible for the toxic ethanol action. Calmodulin protects by reducing calcium release sensitivity.