Neuronostatin acts via GPR107 to increase cAMP-independent PKA phosphorylation and proglucagon mRNA accumulation in pancreatic α-cells

Am J Physiol Regul Integr Comp Physiol. 2016 Jan 15;310(2):R143-55. doi: 10.1152/ajpregu.00369.2014. Epub 2015 Nov 11.

Abstract

Neuronostatin (NST) is a recently described peptide that is produced from the somatostatin preprohormone in pancreatic δ-cells. NST has been shown to increase glucagon secretion from primary rat pancreatic islets in low-glucose conditions. Here, we demonstrate that NST increases proglucagon message in α-cells and identify a potential mechanism for NST's cellular activities, including the phosphorylation of PKA following activation of the G protein-coupled receptor, GPR107. GPR107 is abundantly expressed in the pancreas, particularly, in rodent and human α-cells. Compromise of GPR107 in pancreatic α-cells results in failure of NST to increase PKA phosphorylation and proglucagon mRNA levels. We also demonstrate colocalization of GPR107 and NST on both mouse and human pancreatic α-cells. Taken together with our group's observation that NST infusion in conscious rats impairs glucose clearance in response to a glucose challenge and that plasma levels of the peptide are elevated in the fasted compared with the fed or fasted-refed state, these studies support the hypothesis that endogenous NST regulates islet cell function by interacting with GPR107 and initiating signaling in glucagon-producing α-cells.

Keywords: GPR107; cAMP-independent PKA activation; glucagon; glucose homeostasis; islet function; neuronostatin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Glucagon-Secreting Cells / drug effects*
  • Glucagon-Secreting Cells / enzymology
  • Humans
  • Male
  • Mice
  • Peptide Fragments / metabolism
  • Peptide Hormones / metabolism
  • Peptide Hormones / pharmacology*
  • Phosphorylation
  • Proglucagon / genetics*
  • RNA Interference
  • RNA, Messenger / genetics*
  • Rats, Sprague-Dawley
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction / drug effects
  • Somatostatin / metabolism
  • Transfection
  • Up-Regulation

Substances

  • GPR107 protein, mouse
  • GPR107 protein, rat
  • Peptide Fragments
  • Peptide Hormones
  • RNA, Messenger
  • Receptors, G-Protein-Coupled
  • neuronostatin protein, rat
  • neuronostatin, human
  • neuronostatin, mouse
  • Somatostatin
  • Proglucagon
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases