GABA Coordinates with Insulin in Regulating Secretory Function in Pancreatic INS-1 β-Cells 英文参考文献.docVIP

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GABA Coordinates with Insulin in Regulating Secretory Function in Pancreatic INS-1 β-Cells 英文参考文献.doc

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GABA Coordinates with Insulin in Regulating Secretory Function in Pancreatic INS-1 β-Cells 英文参考文献

GABACoordinateswithInsulininRegulatingSecretory FunctioninPancreaticINS-1b-Cells PaulBansal1,2,ShuanglianWang3,4,ShenghaoLiu1,2,Yun-YanXiang3,4,Wei-YangLu3,4* ,Qinghua Wang1,2 * 1Departments of Physiology and Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada, 2Division of Endocrinology and Metabolism, The Keenan Research Centre in the Li Ka-Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada, 3Department of Physiology and Pharmacology, UniversityofWesternOntario,London,Ontario,Canada,4RobartsResearchInstitute,UniversityofWesternOntario,London,Ontario,Canada Abstract Pancreatic islet b-cells produce large amounts of c-aminobutyric acid (GABA), which is co-released with insulin. GABA inhibits glucagon secretion by hyperpolarizing a-cells via type-A GABA receptors (GABAARs). We and others recently reported that islet b-cells also express GABAARs and that activation of GABAARs increases insulin release. Here we investigatetheeffectsofinsulinontheGABA-GABAARsysteminthepancreaticINS-1cellsusingperforated-patchrecording. TheresultsshowedthatGABAproducesarapidinwardcurrentanddepolarizesINS-1cells.However,pre-treatmentofthe cellwithregularinsulin(1mM)suppressedtheGABA-inducedcurrent(IGABA)by43%.Zinc-freeinsulinalsosuppressedIGABA to the same extent of inhibition by regular insulin. The inhibition of IGABA occurs within 30 seconds after application of insulin. The insulin-induced inhibition of IGABA persisted in the presence of PI3-kinase inhibitor, but was abolished upon inhibition of ERK, indicating that insulin suppresses GABAARs through a mechanism that involves ERK activation. RadioimmunoassayrevealedthatthesecretionofC-peptidewasenhancedbyGABA,whichwasblockedbypre-incubating the cells with picrotoxin (50mM, p,0.01) and insulin (1mM, p,0.01), respectively. Together, these data suggest that autocrineGABA,viaactivationofGABAARs,depolarizesthepancreaticb-cellsandenhancesinsulinsecretion.Ontheother hand,insulindown-regul