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Inhibition of Glucose-Stimulated Activation of Extracellular Signal–Regulated Protein Kinases 1 and 2 by Epinephrine in Pancreatic ß-Cells

¹ Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas
² Departments of Pharmacology and Cellular and Molecular Physiology, Yale University, New Haven, Connecticut
³ cGMP Islet Cell Processing Laboratory, Islet Cell Transplant Program, Baylor University Medical Center, Dallas, Texas

Address correspondence and reprint requests to Melanie H. Cobb, Department of Pharmacology, UT Southwestern Medical Center, 6001 Forest Park Rd., Dallas, TX 75390-9041. E-mail: melanie.cobb{at}utsouthwestern.edu

Abbreviations: ER, endoplasmic reticulum; ERK1/2, extracellular signal–regulated kinases 1 and 2; GLP, glucagon-like peptide; KRBH, Krebs-Ringer bicarbonate HEPES; MAP, mitogen-activated protein; PKA, protein kinase A; SERCA, sarcoplasmic reticulum/endoplasmic reticulum ATPase

Glucose sensing is essential for the ability of pancreatic ß-cells to produce insulin in sufficient quantities to maintain blood glucose within the normal range. Stress causes the release of adrenergic hormones that increase circulating glucose by promoting glucose production and inhibiting insulin release. We have shown that extracellular signal–regulated kinases 1 and 2 (ERK1/2) are responsive to glucose in pancreatic ß-cells and that glucose activates ERK1/2 by mechanisms independent of insulin. Here we show that glucose-induced activation of ERK1/2 is inhibited by epinephrine through the ₂-adrenergic receptor. Epinephrine and the selective ₂-adrenergic agonist UK14304 reduced insulin secretion and glucose-stimulated ERK1/2 activation in a pertussis toxin–sensitive manner, implicating the subunit of a Gi family member. ₂-adrenergic agonists also reduced stimulation of ERK1/2 by glucagon-like peptide 1 and KCl, but not by phorbol ester or nerve growth factor. Our findings suggest that ₂-adrenergic agonists act via a Gi family member on early steps in ERK1/2 activation, supporting the idea that ERK1/2 are regulated in a manner that reflects insulin demand.

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