VAMP8 is the v-SNARE that mediates basolateral exocytosis in a mouse model of alcoholic pancreatitis
VAMP8 is the v-SNARE that mediates basolateral exocytosis in a mouse model of alcoholic pancreatitis
复制标题
DOI：
10.1172/jci34672
复制
发表时间：
2008-07-01
影响因子：
15.9
通讯作者：
Gaisano, Herbert Y.
中科院分区：
文献类型：
--
作者：
Cosen-Binker, Laura I.;Binker, Marcelo G.;Gaisano, Herbert Y.
在啮齿类动物和人类中，酒精暴露已被证明使胰腺易于胆碱能或病毒诱导胰腺炎。我们以前开发了一种啮齿动物模型，其中暴露于乙醇（EtOH）饮食，然后卡巴胆碱（Cch）刺激，重定向胞吐作用从顶端到基底侧的腺泡细胞质膜。导致异位酶原酶激活和胰腺炎。这种胞吐作用的重定向涉及由突触融合蛋白-4和23 kDa的突触相关蛋白（SNAP-23）组成的可溶性NSF附着受体（SNARE）复合物。在这里，我们研究了酶原颗粒（ZG）陷阱囊泡相关膜蛋白8（VAMP 8）介导基底外侧胞吐的作用。在野生型小鼠，在体外乙醇暴露或乙醇饮食减少Cch刺激的淀粉酶释放重定向顶端胞吐作用的基底外侧膜，导致酒精性胰腺炎。在Vamp 8（-/-）小鼠中观察到对这些治疗的反应，进一步减少酶原分泌，这是由顶端和基底外侧胞吐作用的阻断引起的，并导致更轻度的酒精性胰腺炎诱导。此外，尽管ZG在Vamp 8（-/-）腺泡细胞中积累，但与WT腺泡细胞中的那些相比，ZG-ZG融合减少，如通过电子显微镜观察到的。ZG融合的这种减少可以解释Vamp 8（-/-）腺泡中顶端胞吐的效率降低。这些发现表明，VAMP 8是ZG-SNARE，介导酒精性胰腺炎中的基底外侧胞吐，并且VAMP 8对于ZG-ZG同型融合至关重要。
In rodents and humans, alcohol exposure has been shown to predispose the pancreas to cholinergic or viral induction of pancreatitis. We previously developed a rodent model in which exposure to an ethanol (EtOH) diet, followed by carbachol (Cch) stimulation, redirects exocytosis from the apical to the basolateral plasma membrane of acinar cells. resulting in ectopic zymogen enzyme activation and pancreatitis. This redirection of exocytosis involves a soluble NSF attachment receptor (SNARE) complex consisting of syntaxin-4 and synapse-associated protein of 23 kDa (SNAP-23). Here, we investigated the role of the zymogen granule (ZG) SNARE vesicle-associated membrane protein 8 (VAMP8) in mediating basolateral exocytosis. In WT mice, in vitro EtOH exposure or EtOH diet reduced Cch-stimulated amylase release by redirecting apical exocytosis to the basolateral membrane, leading to alcoholic pancreatitis. Further reduction of zymogen secretion, caused by blockade of both apical and basolateral exocytosis and resulting in a more mild induction of alcoholic pancreatitis, was observed in Vamp8(-/-) mice in response to these treatments. In addition, although ZGs accumulated in Vamp8(-/-) acinar cells, ZG-ZG fusions were reduced compared with those in WT acinar cells, as visualized by electron microscopy. This reduction in ZG fusion may account for reduced efficiency of apical exocytosis in Vamp8(-/-) acini. These findings indicate that VAMP8 is the ZG-SNARE that mediates basolateral exocytosis in alcoholic pancreatitis and that VAMP8 is critical for ZG-ZG homotypic fusion.