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

Michael A Kalwat,Zhimin Huang,Melanie H Cobb,Derk D Binns,Kathleen Mcglynn

doi:10.3389/fcell.2020.576396

Abstract

Adrenergic signaling is a well-known input into pancreatic islet function. Specifically, the insulin-secreting islet β cell expresses the Gi/o-linked α2-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 Gi/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.

Highlights

Glucose homeostasis is largely controlled by the metered secretion of insulin from pancreatic islet β cells. β cells respond to elevated circulating glucose via coupling its metabolism to membrane depolarization, calcium (Ca2+) influx, and insulin exocytosis (Kalwat and Cobb, 2017)
In our studies of β cell Extracellular regulated kinase 1/2 (ERK1/2) activation, we noted an interaction between signaling downstream of receptor tyrosine kinases (RTKs) and α2-adrenergic receptor stimulation
Pretreatment with epinephrine for 15 min blocked downstream phosphorylation of ERK1/2 to varying degrees depending on the RTK in question (Figure 1A)

Summary

Introduction

Glucose homeostasis is largely controlled by the metered secretion of insulin from pancreatic islet β cells. β cells respond to elevated circulating glucose via coupling its metabolism to membrane depolarization, calcium (Ca2+) influx, and insulin exocytosis (Kalwat and Cobb, 2017). Glucose homeostasis is largely controlled by the metered secretion of insulin from pancreatic islet β cells. Secreted insulin suppresses liver gluconeogenesis and stimulates peripheral glucose uptake. Β cells are Epinephrine Suppresses β-Cell TrkB Signaling either destroyed by the immune system (type 1 diabetes) or unable to secrete sufficient insulin in response to stimulation (type 2 diabetes). Β cells utilize a variety of signaling mechanisms such as G-protein-coupled receptors (GPCRs) (Holst, 2007; Straub and Sharp, 2012) and receptor tyrosine kinases (RTKs) (Kulkarni et al, 1999, 2002; Song et al, 2016). Reported cross talk between GLP1R and EGFR in islet β cells lends support to the idea of more general GPCR-RTK signaling interactions in β cells (Fusco et al, 2017)

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Conclusion