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

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology Vol. 310; no. 2; pp. R143 - R155
• Main Authors: Elrick, Mollisa M, Samson, Willis K, Corbett, John A, Salvatori, Alison S, Stein, Lauren M, Kolar, Grant R, Naatz, Aaron, Yosten, Gina L C
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 15.01.2016
• Subjects: Animals; Cell Line; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Glucagon-Secreting Cells - drug effects; Glucagon-Secreting Cells - enzymology; Humans; Male; Mice; Obesity, Diabetes and Energy Homeostasis; Peptide Fragments - metabolism; Peptide Hormones - metabolism; Peptide Hormones - pharmacology; Phosphorylation; Proglucagon - genetics; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; RNA Interference; RNA, Messenger - genetics; Signal Transduction - drug effects; Somatostatin - metabolism; Transfection; Up-Regulation; cAMP-independent PKA activation; glucose homeostasis; glucagon; neuronostatin; GPR107; islet function
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00369.2014

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.