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XB-ART-40100
Gastroenterology 2009 Aug 01;1372:607-17, 617.e1-4. doi: 10.1053/j.gastro.2009.01.065.
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Synaptic scaffolding molecule binds to and regulates vasoactive intestinal polypeptide type-1 receptor in epithelial cells.

Gee HY , Kim YW , Jo MJ , Namkung W , Kim JY , Park HW , Kim KS , Kim H , Baba A , Yang J , Kim E , Kim KH , Lee MG .


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BACKGROUND & AIMS: Vasoactive intestinal polypeptide (VIP) is a principal regulator of fluid and electrolyte secretion in the gastrointestinal system. The VIP type-1 receptor (VPAC1), a class II G-protein-coupled receptor, contains a putative C-terminal PDZ-binding motif. A yeast 2-hybrid screen indicated that the C-terminus of VPAC1 bound to the PDZ domain of synaptic scaffolding molecule (S-SCAM, also known as membrane-associated guanylate kinase inverted-2 [MAGI-2]). We analyzed the association between S-SCAM and VPAC1. METHODS: The biochemical properties and physiologic significance of the interaction between VPAC1 and S-SCAM were examined in heterologous expression systems, T84 colonic epithelial cells, and human pancreas and colon tissues using an integrated molecular and physiologic approach. RESULTS: The physical interaction between VPAC1 and S-SCAM was confirmed by immunoprecipitation in HEK 293 mammalian cells and human pancreatic and colonic tissues. Immunocytochemical analysis indicated that S-SCAM recruited VPAC1 to the junctional area near the apical end of the lateral membrane in T84 cells. Several lines of evidence revealed that S-SCAM inhibits VPAC1 activation. Overexpression of S-SCAM inhibited VPAC1-mediated cAMP production and agonist-induced VPAC1 internalization in HEK 293 and HeLa cells. In addition, S-SCAM decreased the VPAC1-mediated current through the cystic fibrosis transmembrane conductance regulator in Xenopus oocytes, especially at low concentrations of VIP. Importantly, loss of S-SCAM increased VIP-induced short-circuit currents in T84 monolayers, which endogenously express VPAC1 and S-SCAM. CONCLUSIONS: S-SCAM/MAGI-2 interacts with and regulates VPAC1 intracellular localization in epithelial cells and inhibits VPAC1 agonist-induced activation and internalization.

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Species referenced: Xenopus
Genes referenced: camp vip vipr1