Trace amine-associated receptor 1 (TAAR1) promotes anti-diabetic signaling in insulin-secreting cells [Metabolism]

Pancreatic β-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 β-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 Gαs-signaling pathways in insulin-secreting β-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 β-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/Gαs-mediated signaling pathways that promote insulin secretion, improved β-cell function and proliferation, and highlight TAAR1 as a promising new target for improving β-cell health in type 2 diabetes mellitus.
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Signal Transduction Source Type: research