Cosen-Binker Laura I, Lam Patrick P L, Binker Marcelo G, Gaisano Herbert Y
Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Gastroenterology. 2007 Apr;132(4):1527-45. doi: 10.1053/j.gastro.2007.01.042. Epub 2007 Jan 26.
BACKGROUND & AIMS: Acute or chronic alcohol treatment does little to the exocrine pancreas but predisposes the pancreas to postprandial cholinergic stimulation that triggers cellular events leading to pancreatitis. This alcohol-induced susceptibility mechanism of pancreatitis is unknown.
We employed alcohol-treated dispersed rat pancreatic acini and alcohol diet-fed rats to examine the effects of submaximal carbachol-induced changes in exocytosis (FM1-43 epifluorescence imaging and electron microscopy), Munc18c cellular translocation (confocal microscopy and subcellular fractionation), and protein kinase C (PKC) alpha-induced phosphorylation in relation to pancreatitis.
Acute low-dose alcohol (20 mmol/L) in vitro exposure or chronic alcohol diet reduces postprandial cholinergic-stimulated amylase secretion from rat pancreatic acinar cells by blocking apical exocytosis and redirecting exocytosis to less efficient basolateral plasma membrane sites. This ectopic exocytosis is mediated by PKCalpha-induced phosphorylation of Munc18c, causing Munc18c displacement from the basolateral plasma membrane into the cytosol in which it undergoes proteolytic degradation; these processes can be blocked by PKCalpha inhibition.
We conclude that sequential low-dose alcohol and postprandial cholinergic stimulation can induce PKCalpha-mediated Munc18c plasma membrane displacement. This relieves cognate SNARE proteins on zymogen granules and basolateral membrane to complex and consummate pathologic ectopic exocytosis at the basolateral surface. This change in vesicle trafficking may be related to the pathogenesis of pancreatitis.
急性或慢性酒精处理对外分泌胰腺影响不大，但会使胰腺易受餐后胆碱能刺激，从而引发导致胰腺炎的细胞事件。这种酒精诱导的胰腺炎易感性机制尚不清楚。
我们使用经酒精处理的分散大鼠胰腺腺泡和喂食酒精饮食的大鼠，来研究次最大剂量卡巴胆碱诱导的胞吐作用变化（FM1-43 落射荧光成像和电子显微镜）、Munc18c 细胞易位（共聚焦显微镜和亚细胞分级分离）以及蛋白激酶 C（PKC）α诱导的磷酸化与胰腺炎的关系。
体外急性低剂量酒精（20 mmol/L）暴露或慢性酒精饮食通过阻断顶端胞吐作用并将胞吐作用重定向至效率较低的基底外侧质膜部位，降低了大鼠胰腺腺泡细胞餐后胆碱能刺激的淀粉酶分泌。这种异位胞吐作用由 PKCα诱导的 Munc18c 磷酸化介导，导致 Munc18c 从基底外侧质膜移位至胞质溶胶，在其中它会经历蛋白水解降解；这些过程可被 PKCα抑制所阻断。
我们得出结论，序贯低剂量酒精和餐后胆碱能刺激可诱导 PKCα介导的 Munc18c 质膜移位。这使酶原颗粒和基底外侧膜上的同源 SNARE 蛋白得以解脱，从而在基底外侧表面形成并完成病理性异位胞吐作用。这种囊泡运输的变化可能与胰腺炎的发病机制有关。
