title: Neuronostatin acts via GPR107 to increase cAMP-independent PKA phosphorylation and proglucagon mRNA accumulation in pancreatic α-cells.
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.
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri;
authors.forename: Mollisa M
authors.initials: MM
authors.lastname: Elrick
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri;
authors.forename: Willis K
authors.initials: WK
authors.lastname: Samson
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: John A
authors.initials: JA
authors.lastname: Corbett
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri;
authors.forename: Alison S
authors.initials: AS
authors.lastname: Salvatori
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri;
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Stein
authors.affiliation: Department of Pathology, Saint Louis University School of Medicine, St. Louis, Missouri; and.
authors.forename: Grant R
authors.initials: GR
authors.lastname: Kolar
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Aaron
authors.initials: A
authors.lastname: Naatz
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri; gyosten@slu.edu.
authors.forename: Gina L C
authors.initials: GL
authors.lastname: Yosten
mesh_terms: D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008297:Male; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism; D036361:Peptide Hormones / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation; D052336:Proglucagon / Q000235:genetics*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics*; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013004:Somatostatin / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
chemical_list: C579288:GPR107 protein, mouse; C579287:GPR107 protein, rat; D010446:Peptide Fragments; D036361:Peptide Hormones; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C554543:neuronostatin protein, rat; C579289:neuronostatin, human; C543371:neuronostatin, mouse; D013004:Somatostatin; D052336:Proglucagon; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: GPR107; cAMP-independent PKA activation; glucagon; glucose homeostasis; islet function; neuronostatin