BDNF/TrkB signaling in pancreatic islet beta cells

ABSTRACT Brain-derived neurotrophic factor (BDNF) is a secreted hormone present in the blood that is an essential participant in whole body energy homeostasis. The best characterized actions of BDNF and its receptor tyrosine kinase, TrkB, are in synaptic plasticity, learning and memory in the nervous system. TrkB is also expressed in multiple other tissues including human and rodent pancreatic islets. Because little is known about BDNF signaling in pancreatic islet cell types, we examined activation of ERK1/2 by BDNF and interactions with regulators of insulin secretion. Both MIN6 β cells and αTC1-9 α cells responded to physiological BDNF concentrations. ERK1/2 were no longer activated by BDNF in TrkB-deleted cells; signaling to ERK1/2 was restored in these cells by re-expression of full-length TrkB, confirming that TrkB is required for BDNF signaling. BDNF potentiated activation of ERK1/2 by glucose and GLP-1 in MIN6 cells without detectably altering cAMP. Activation of ERK1/2 by BDNF was independent of calcium influx but required Raf1; however ERK activation by BDNF was blocked by epinephrine, an inhibitor of insulin secretion, in a Gi/o-dependent manner. Surprisingly, epinephrine also blocked BDNF-induced tyrosine phosphorylation of TrkB. We conclude that BDNF acting through its receptor TrkB has previously unrecognized functions in endocrine cells of the pancreas.