MOLECULAR MECHANISM OF GLP-1 POTENTIATED INSULIN GRANULE EXOCYTOSIS
NEHA SHRESTHA
NEHA SHRESTHA
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Abstract
GLUCAGON-LIKE PEPTIDE-1 (GLP-1) BASED DRUGS ARE WIDELY USED TO POTENTIATE INSULIN SECRETION AND IMPROVE METABOLIC CONTROL IN DIABETICS; HOWEVER, MOLECULAR MECHANISMS UNDERLYING GLP-1 POTENTIATION OF INSULIN SECRETION REMAIN UNCLEAR. PHOSPHORYLATION OF SYNAPTOTAGMIN7 (SYT7) BY PKA IS ESSENTIAL FOR GLP-1 POTENTIATION OF INSULIN RELEASE. USING PROTEOMICS APPROACH, WE FOUND THAT THE PHOSPHOMIMETIC FORM OF SYT7 EXHIBITS ENHANCED BINDING TO RABPHILIN3A (RPH3A). KNOCKDOWN OF ENDOGENOUS RPH3A FROM MIN6 CELLS DIMINISHED FORSKOLIN INDUCED INSULIN RELEASE WHILE OVEREXPRESSION OF PHOSPHOMIMETIC RPH3A (S234E) IN MOUSE ISLETS ENHANCED GLP-1 MEDIATED INSULIN SECRETION. INTERESTINGLY, MYOSIN VA- A MOTOR PROTEIN, ALSO COIMMUNOPRECIPITATED WITH SYT7 AND RPH3A UPON ACTIVATION OF PKA SIGNALING. KNOCKDOWN OF MYOVA DIMINISHED FORSKOLIN INDUCED INSULIN RELEASE. TOGETHER, OUR RESULTS SUGGEST THAT PHOSPHORYLATION OF SYT7 BY GLP-1 PROMOTES INSULIN GRANULE EXOCYTOSIS BY ENHANCING GRANULE TRANSLOCATION VIA ITS IN
Keywords
Exocytosis, Insulin, GLP-1, Synaptotagmin, Rabphilin
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Date
2015-08-03
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Thesis