Alcohol/Cholecystokinin-evoked Pancreatic Acinar Basolateral Exocytosis Is Mediated by Protein Kinase Cα Phosphorylation of Munc18c

Cosen-Binker, Laura Iris; Lam, Patrick; Binker, Marcelo Gustavo; Reeve, Joseph R.; Pandol, Stephen J.; Gaisano, Herbert Y.

doi:10.1074/jbc.m611132200

Cited by 65 publications

(75 citation statements)

References 33 publications

(36 reference statements)

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“…Using a rat model of a 6-week ethanol (EtOH) diet (ED) that resulted in blood alcohol levels equivalent to those seen in clinical intoxication (5), followed by i.p. injections of submaximal concentrations of Cch or CCK simulating postprandial stimulation, we observed apical blockade and a redirection of exocytosis to the basolateral PM as well as pancreatitis (6)(7)(8). In those studies we began to reveal the putative molecules that mediate basolateral exocytosis, which we found to be consistent with the paradigm of the "SNARE hypothesis" (9,10).…”

Section: Introductionsupporting

confidence: 64%

“…Instead, Vamp8 deletion resulted in inhibition of agonist-stimulated secretion, not only in pancreatic acinar cells (15) but also in other exocrine tissues (20). While these reports collectively suggest the role of Vamp8 in apical exocytosis, Vamp8 deletion also abrogated supramaximal CCK-induced pancreatitis (15), which when taken in the context of our recent work (4,(6)(7)(8) would suggest a possible role for Vamp8 in basolateral exocytosis as well. Nonetheless, the precise role of Vamp8 in each of these exocytotic compartments has not been unequivocally demonstrated.…”

Section: Introductionmentioning

confidence: 58%

“…Specifically, Munc18c bound syntaxin-4 (Syn-4) on the basolateral PM, which prevented Syn-4 binding to cognate soluble NSF attachment receptor (SNARE) proteins (4,(6)(7)(8). ED or EtOH pretreatment of acini followed by submaximal Cch (6) or CCK stimulation (7,8) induced PKCα-mediated threonine phosphorylation of Munc18c, which caused its displacement from Syn-4, and activated Syn-4 assembly with synapse-associated protein of 23 kDa (SNAP-23) and vesicle-associated membrane protein (VAMP) proteins to form the SNARE complex that we postulated to mediate basolateral exocytosis.…”

Section: Introductionmentioning

confidence: 99%

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VAMP8 is the v-SNARE that mediates basolateral exocytosis in a mouse model of alcoholic pancreatitis

Cosen-Binker¹,

Binker²,

Wang³

et al. 2008

J. Clin. Invest.

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117

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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 synapseassociated 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.

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Section: Introductionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

VAMP8 is the v-SNARE that mediates basolateral exocytosis in a mouse model of alcoholic pancreatitis

Cosen-Binker¹,

Binker²,

Wang³

et al. 2008

J. Clin. Invest.

Self Cite

117

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“…ATP is also needed for calcium homeostasis and decreased ATP levels cause further increases in pathological calcium levels in the cytosol (Criddle et al, 2006). Downstream targets of calcium include Protein-Kinase C (PKC) and the calcium-sensitive phosphatase calcineurin Satoh et al, 2004;Cosen-Binker et al, 2007;Thrower et al, 2008Thrower et al, , 2009Muili et al, 2012). FK506 (Tacrolimus), a macrolide immunosuppressant that inhibits calcineurin has been shown to markedly reduce intra-pancreatic protease activation and pancreatitis severity in cerulein models of pancreatitis Muili et al, 2012).…”

Section: Calcium Signalingmentioning

confidence: 99%

Risk Factors for Pancreatic Cancer: Underlying Mechanisms and Potential Targets

2015

Frontiers Research Topics

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Purpose of the review: Pancreatic cancer is extremely aggressive, forming highly chemo-resistant tumors, and has one of the worst prognoses. The evolution of this cancer is multi-factorial. Repeated acute pancreatic injury and inflammation are important contributing factors in the development of pancreatic cancer. This article attempts to understand the common pathways linking pancreatitis to pancreatic cancer.Recent findings: Intracellular activation of both pancreatic enzymes and the transcription factor NF-κB are important mechanisms that induce acute pancreatitis (AP). Recurrent pancreatic injury due to genetic susceptibility, environmental factors such as smoking, alcohol intake, and conditions such as obesity lead to increases in oxidative stress, impaired autophagy and constitutive activation of inflammatory pathways. These processes can stimulate pancreatic stellate cells, thereby increasing fibrosis and encouraging chronic disease development. Activation of oncogenic Kras mutations through inflammation, coupled with altered levels of tumor suppressor proteins (p53 and p16) can ultimately lead to development of pancreatic cancer.Summary: Although our understanding of pancreatitis and pancreatic cancer has tremendously increased over many years, much remains to be elucidated in terms of common pathways linking these conditions.

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“…It is widely recognized that the intracellular pathways followed by secretory proteins in epithelial cells are directed by a large repertoire of carefully regulated molecules (Rodriguez-Boulan et al, 2005). Thus, there are numerous intracellular steps wherein a genetic or metabolic change could lead to a difference in the final destination of the transgenic protein (Folsch et al, 1999;Cosen-Binker et al, 2007.…”

Section: Figmentioning

confidence: 99%

Differential Sorting of Human Parathyroid Hormone After Transduction of Mouse and Rat Salivary Glands

et al. 2008

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Gene transfer to salivary glands leads to abundant secretion of transgenic protein into either saliva or the bloodstream. This indicates significant clinical potential, depending on the route of sorting. The aim of this study was to probe the sorting characteristics of human parathyroid hormone (hPTH) in two animal models for salivary gland gene transfer. PTH is a key hormone regulating calcium levels in the blood. A recombinant serotype 5 adenoviral vector carrying the hPTH cDNA was administered to the submandibular glands of mice and rats. Two days after delivery, high levels of hPTH were found in the serum of mice, leading to elevated serum calcium levels. Only low amounts of hPTH were found in the saliva. Two days after vector infusion into rats, a massive secretion of hPTH was measured in saliva, with little secretion into serum. Confocal microscopy showed hPTH in the glands, localized basolaterally in mice and apically in rats. Submandibular gland transduction was effective and the produced hPTH was biologically active in vivo. Whereas hPTH sorted toward the basolateral side in mice, in rats hPTH was secreted mainly at the apical side. These results indicate that the interaction between hPTH and the cell sorting machinery is different between mouse and rat salivary glands. Detailed studies in these two species should result in a better understanding of cellular control of transgenic secretory protein sorting in this tissue.

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Alcohol/Cholecystokinin-evoked Pancreatic Acinar Basolateral Exocytosis Is Mediated by Protein Kinase Cα Phosphorylation of Munc18c

Cited by 65 publications

References 33 publications

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

Risk Factors for Pancreatic Cancer: Underlying Mechanisms and Potential Targets

Differential Sorting of Human Parathyroid Hormone After Transduction of Mouse and Rat Salivary Glands

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