α2-Adrenergic Disruption of β Cell BDNF-TrkB Receptor Tyrosine Kinase Signaling

Abstract

Adrenergic signaling is a well-known input into pancreatic islet function. Specifically, the insulin-secreting islet β cell expresses the G i/o -linked α 2 -adrenergic receptor, which upon activation suppresses insulin secretion. The use of the adrenergic agonist epinephrine at micromolar doses may have supraphysiological effects. We found that pretreating β cells with micromolar concentrations of epinephrine differentially inhibited activation of receptor tyrosine kinases. We chose TrkB as an example because of its relative sensitivity to the effects of epinephrine and due to its potential regulatory role in the β cell. Our characterization of brain-derived neurotrophic factor (BDNF)-TrkB signaling in MIN6 β cells showed that TrkB is activated by BDNF as expected, leading to canonical TrkB autophosphorylation and subsequent downstream signaling, as well as chronic effects on β cell growth. Micromolar, but not nanomolar, concentrations of epinephrine blocked BDNF-induced TrkB autophosphorylation and downstream mitogen-activated protein kinase pathway activation, suggesting an inhibitory phenomenon at the receptor level. We determined epinephrine-mediated inhibition of TrkB activation to be G i/o -dependent using pertussis toxin, arguing against an off-target effect of high-dose epinephrine. Published data suggested that inhibition of potassium channels or phosphoinositide-3-kinase signaling may abrogate the negative effects of epinephrine; however, these did not rescue TrkB signaling in our experiments. Taken together, these results show that (1) TrkB kinase signaling occurs in β cells and (2) use of epinephrine in studies of insulin secretion requires careful consideration of concentration-dependent effects. BDNF-TrkB signaling in β cells may underlie pro-survival or growth signaling and warrants further study.

Type I Diabetes Pathoetiology and Pathophysiology: Roles of the Gut Microbiome, Pancreatic Cellular Interactions, and the ‘Bystander’ Activation of Memory CD8+ T Cells

“…Recent data implicate BDNF activation of TrkB in driving trophic and protective effects in pancreatic β-cells [ 122 ]. This would indicate that the autocrine and paracrine effects of released NAS would similarly have protective effects in pancreatic β-cells.…”

“…Such data on the role of BDNF in pancreatic β-cells [ 118 , 122 ] may have a number of implications for alterations in the tryptophan–melatonin pathway in T1DM. The relevance of different cellular sources of NAS, and NAS-induced BDNF [ 123 ], will be important to determine in pancreatic islets, not only from pancreatic β-, α-, δ-, and ε-cells, but also from other cells in the pancreatic islet microenvironment, including macrophages and other immune cells, as well as circulating cells such as platelets.…”

“…During brain development and in amyotrophic lateral sclerosis motor neuron loss, the induction of the truncated TrkB-T1 seems important to prevent BDNF and NAS trophic and metabolic support to cells [ 7 ]. Data in pancreatic β-cells do show BDNF, via TrkB-T1, to provide trophic support to pancreatic β-cells [ 118 ], although other data show that trophic support in pancreatic β-cells is provided mainly by TrkB-FL [ 122 ]. This requires independent investigation, including as to the role of alterations in mitochondrial metabolism in pancreatic β-cells as driven by a suppressed melatonergic pathway, leading to enhanced mitochondrial ROS and ROS-driven miRNAs, and therefore altered gene patterning.…”

“…The dependence of pancreatic β-cells on TrkB-FL [ 122 ] and TrkB-T1 [ 118 ] highlights the importance of BDNF signaling, including from muscle activity, in the maintenance of optimized pancreatic β-cell function and insulin release. These data also strongly implicate variations in the melatonergic pathway, specifically the factors regulating the NAS/melatonin ratio, including kynurenine at the AhR, ATP at the P2Y1r, and glutamate at the mGluR5.…”

Brain-Derived Neurotrophic Factor And Coronary Artery Disease

“…The BDNF TrkB receptor is expressed by pancreatic β-cells; therefore, BDNF induces insulin secretion via interacting with this receptor [54][55][56]. It is currently acknowledged that altered levels of BDNF form the basis for the pathogenesis of diabetes mellitus [14,57].…”