期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 294, 期 12, 页码 4401-4411出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.005464
关键词
diabetes; calcium; pancreas; G protein-coupled receptor (GPCR); insulin secretion
资金
- NIDDK, National Institutes of Health [DK101240]
Pancreatic -cell failure in type 2 diabetes mellitus is a serious challenge that results in an inability of the pancreas to produce sufficient insulin to properly regulate blood glucose levels. Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor expressed by -cells that has recently been proposed as a potential target for improving glycemic control and suppressing binge eating behaviors. We discovered that TAAR1 is coupled to G(s)-signaling pathways in insulin-secreting -cells to cause protein kinase A (PKA)/exchange protein activated by cAMP (Epac)-dependent release of insulin, activation of RAF proto-oncogene, Ser/Thr kinase (Raf)-mitogen-activated protein kinase (MAPK) signaling, induction of cAMP response element-binding protein (CREB)-insulin receptor substrate 2 (Irs-2), and increased -cell proliferation. Interestingly, TAAR1 triggered cAMP-mediated calcium influx and release from internal stores, both of which were required for activation of a MAPK cascade utilizing calmodulin-dependent protein kinase II (CaMKII), Raf, and MAPK/ERK kinase 1/2 (MEK1/2). Together, these data identify TAAR1/G(s)-mediated signaling pathways that promote insulin secretion, improved -cell function and proliferation, and highlight TAAR1 as a promising new target for improving -cell health in type 2 diabetes mellitus.
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