{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:32:45Z","timestamp":1790803965455,"version":"4.1.0"},"reference-count":45,"publisher":"The Endocrine Society","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>l-Arginine (l-Arg) is an insulin secretagogue, but the molecular mechanism whereby it stimulates insulin secretion from \u03b2-cells is not known. The possibility that l-Arg regulates insulin secretion through a G protein-coupled receptor (GPCR)-mediated mechanism is suggested by the high expression of the nutrient receptor GPCR family C group 6 member A (GPRC6A) in the pancreas and TC-6 \u03b2-cells and the finding that Gprc6a\u2212\/]minus] mice have abnormalities in glucose homeostasis. To test the direct role of GPRC6A in regulating insulin secretion, we evaluated the response of pancreatic islets derived from Gprc6a\u2212\/]minus] mice to l-Arg. We found that the islet size and insulin content were decreased in pancreatic islets from Gprac6a\u2212\/]minus] mice. These alterations were selective for \u03b2-cells, because there were no abnormalities in serum glucagon levels or glucagon content of islets derived from Gprac6a\u2212\/]minus] mice. Significant reduction was observed in both the pancreatic ERK response to l-Arg administration to Gprc6a\u2212\/]minus] mice in vivo and l-Arg-induced insulin secretion and production ex vivo in islets isolated from Gprc6a\u2212\/]minus] mice. l-Arg stimulation of cAMP accumulation in isolated islets isolated from Gprc6a\u2212\/]minus] mice was also diminished. These findings suggest that l-Arg stimulation of insulin secretion in \u03b2-cells is mediated, at least in part, through GPRC6A activation of cAMP pathways.<\/jats:p>","DOI":"10.1210\/en.2012-1301","type":"journal-article","created":{"date-parts":[[2012,9,21]],"date-time":"2012-09-21T17:45:03Z","timestamp":1348249503000},"page":"4608-4615","source":"Crossref","is-referenced-by-count":74,"title":["GPRC6A Mediates the Effects of l-Arginine on Insulin Secretion in Mouse Pancreatic Islets"],"prefix":"10.1210","volume":"153","author":[{"given":"Min","family":"Pi","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunpeng","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nataliya I","family":"Lenchik","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Gerling","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. Darryl","family":"Quarles","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071612125474500_B1","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.pharmthera.2007.08.002","article-title":"G-protein-coupled receptors and islet function: implications for treatment of type 2 diabetes.","volume":"116","author":"Winzell","year":"2007","journal-title":"Pharmacol Ther"},{"key":"2020071612125474500_B2","first-page":"4034","article-title":"Probing cell type-specific functions of Gi in vivo identifies GPCR regulators of insulin secretion.","volume":"117","author":"Regard","year":"2007","journal-title":"J Clin Invest"},{"key":"2020071612125474500_B3","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1002\/jcb.20500","article-title":"Osteoblast calcium-sensing receptor has characteristics of ANF\/7TM receptors.","volume":"95","author":"Pi","year":"2005","journal-title":"J Cell Biochem"},{"key":"2020071612125474500_B4","doi-asserted-by":"crossref","first-page":"e3858","DOI":"10.1371\/journal.pone.0003858","article-title":"GPRC6A null mice exhibit osteopenia, feminization and metabolic syndrome.","volume":"3","author":"Pi","year":"2008","journal-title":"PLoS ONE"},{"key":"2020071612125474500_B5","doi-asserted-by":"crossref","first-page":"40201","DOI":"10.1074\/jbc.M505186200","article-title":"Identification of a novel extracellular cation-sensing G-protein-coupled receptor.","volume":"280","author":"Pi","year":"2005","journal-title":"J Biol Chem"},{"key":"2020071612125474500_B6","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/366575a0","article-title":"Cloning and characterization of an extracellular Ca2+-sensing receptor from bovine parathyroid.","volume":"366","author":"Brown","year":"1993","journal-title":"Nature"},{"key":"2020071612125474500_B7","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/S0165-6147(99)01323-1","article-title":"GABAB receptors make it to the top: as dimers.","volume":"20","author":"M\u00f6hler","year":"1999","journal-title":"Trends Pharmacol Sci"},{"key":"2020071612125474500_B8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0028-3908(94)00129-G","article-title":"The metabotropic glutamate receptors: structure and functions.","volume":"34","author":"Pin","year":"1995","journal-title":"Neuropharmacology"},{"key":"2020071612125474500_B9","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/nature726","article-title":"An amino-acid taste receptor.","volume":"416","author":"Nelson","year":"2002","journal-title":"Nature"},{"key":"2020071612125474500_B10","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1006\/geno.2000.6226","article-title":"Molecular cloning and characterization of two novel retinoic acid-inducible orphan G-protein-coupled receptors (GPRC5B and GPRC5C).","volume":"67","author":"Robbins","year":"2000","journal-title":"Genomics"},{"key":"2020071612125474500_B11","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1006\/geno.2000.6164","article-title":"Sequence and expression pattern of a novel human orphan G-protein-coupled receptor, GPRC5B, a family C receptor with a short amino-terminal domain.","volume":"65","author":"Br\u00e4uner-Osborne","year":"2000","journal-title":"Genomics"},{"key":"2020071612125474500_B12","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/S0092-8674(01)00451-2","article-title":"Mammalian sweet taste receptors.","volume":"106","author":"Nelson","year":"2001","journal-title":"Cell"},{"key":"2020071612125474500_B13","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/S0169-328X(02)00662-9","article-title":"Molecular cloning and characterisation of a novel GABAB-related G-protein coupled receptor.","volume":"110","author":"Calver","year":"2003","journal-title":"Brain Res Mol Brain Res"},{"key":"2020071612125474500_B14","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1124\/mol.104.007559","article-title":"Deorphanization of GPRC6A: a promiscuous l-\u03b1-amino acid receptor with preference for basic amino acids.","volume":"67","author":"Wellendorph","year":"2005","journal-title":"Mol Pharmacol"},{"key":"2020071612125474500_B15","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.1002\/jbmr.390","article-title":"GPRC6A mediates responses to osteocalcin in \u03b2-cells in vitro and pancreas in vivo.","volume":"26","author":"Pi","year":"2011","journal-title":"J Bone Miner Res"},{"key":"2020071612125474500_B16","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1038\/sj.bjp.0707121","article-title":"Pharmacological characterization of mouse GPRC6A, an l-alpha-amino-acid receptor modulated by divalent cations.","volume":"150","author":"Christiansen","year":"2007","journal-title":"Br J Pharmacol"},{"key":"2020071612125474500_B17","doi-asserted-by":"crossref","first-page":"39953","DOI":"10.1074\/jbc.M110.158063","article-title":"GPRC6A mediates the non-genomic effects of steroids.","volume":"285","author":"Pi","year":"2010","journal-title":"J Biol Chem"},{"key":"2020071612125474500_B18","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1016\/j.cell.2011.02.004","article-title":"Endocrine regulation of male fertility by the skeleton.","volume":"144","author":"Oury","year":"2011","journal-title":"Cell"},{"key":"2020071612125474500_B19","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1359\/jbmr.091037","article-title":"Impaired osteoblast function in GPRC6A null mice.","volume":"25","author":"Pi","year":"2010","journal-title":"J Bone Miner Res"},{"key":"2020071612125474500_B20","first-page":"15","article-title":"Dominant negative effect of the extracellular domain of CASR.","volume":"3","author":"Pi","year":"2010","journal-title":"J Receptor, Ligand Channel Res"},{"key":"2020071612125474500_B21","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1172\/JCI105456","article-title":"Stimulation of insulin secretion by amino acids.","volume":"45","author":"Floyd","year":"1966","journal-title":"J Clin Invest"},{"key":"2020071612125474500_B22","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1055\/s-0029-1234087","article-title":"Evaluation of beta cell dysfunction by mixed meal tolerance test and oral l-arginine in patients with newly diagnosed type 2 diabetes mellitus.","volume":"117","author":"Ozbek","year":"2009","journal-title":"Exp Clin Endocrinol Diabetes"},{"key":"2020071612125474500_B23","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s00726-008-0210-y","article-title":"Arginine metabolism and nutrition in growth, health and disease.","volume":"37","author":"Wu","year":"2009","journal-title":"Amino Acids"},{"key":"2020071612125474500_B24","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1054\/ghir.1999.0089","article-title":"l-Arginine-induced growth hormone secretion is not influenced by co-infusion of the nitric oxide synthase inhibitor N-monomethyl-l-arginine in healthy men.","volume":"9","author":"Fisker","year":"1999","journal-title":"Growth Horm IGF Res"},{"key":"2020071612125474500_B25","doi-asserted-by":"crossref","first-page":"16530","DOI":"10.1074\/jbc.M109.092593","article-title":"The mitochondrial 2-oxoglutarate carrier is part of a metabolic pathway that mediates glucose- and glutamine-stimulated insulin secretion.","volume":"285","author":"Odegaard","year":"2010","journal-title":"J Biol Chem"},{"key":"2020071612125474500_B26","doi-asserted-by":"crossref","first-page":"2558","DOI":"10.1210\/endo-124-5-2558","article-title":"Stimulus-secretion coupling of arginine-induced insulin release: comparison with lysine-induced insulin secretion.","volume":"124","author":"Sener","year":"1989","journal-title":"Endocrinology"},{"key":"2020071612125474500_B27","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1530\/eje.0.1400087","article-title":"l-arginine stimulation of glucose-induced insulin secretion through membrane depolarization and independent of nitric oxide.","volume":"140","author":"Thams","year":"1999","journal-title":"Eur J Endocrinol"},{"key":"2020071612125474500_B28","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/S0092-8674(00)80546-2","article-title":"Tissue-specific knockout of the insulin receptor in pancreatic \u03b2-cells creates an insulin secretory defect similar to that in type 2 diabetes.","volume":"96","author":"Kulkarni","year":"1999","journal-title":"Cell"},{"key":"2020071612125474500_B29","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1002\/(SICI)1526-968X(200002)26:2<139::AID-GENE12>3.0.CO;2-7","article-title":"Analysis of the Cre-mediated recombination driven by rat insulin promoter in embryonic and adult mouse pancreas.","volume":"26","author":"Gannon","year":"2000","journal-title":"Genesis"},{"key":"2020071612125474500_B30","first-page":"3208","article-title":"A new method for isolation of murine islets with markedly improved yields.","volume":"27","author":"Liu","year":"1995","journal-title":"Transplant Proc"},{"key":"2020071612125474500_B31","doi-asserted-by":"crossref","first-page":"1672","DOI":"10.2337\/diab.41.12.1672","article-title":"Intrathymic islet cell transplantation reduces \u03b2-cell autoimmunity and prevents diabetes in NOD\/Lt mice.","volume":"41","author":"Gerling","year":"1992","journal-title":"Diabetes"},{"key":"2020071612125474500_B32","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1038\/nature05315","article-title":"Klotho converts canonical FGF receptor into a specific receptor for FGF23.","volume":"444","author":"Urakawa","year":"2006","journal-title":"Nature"},{"key":"2020071612125474500_B33","doi-asserted-by":"crossref","first-page":"5266","DOI":"10.1073\/pnas.0711119105","article-title":"Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice.","volume":"105","author":"Ferron","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612125474500_B34","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/0014-5793(73)80218-2","article-title":"Activation by glucose of adenyl cyclase in pancreatic islets of the rat.","volume":"33","author":"Grill","year":"1973","journal-title":"FEBS Lett"},{"key":"2020071612125474500_B35","doi-asserted-by":"crossref","first-page":"2062","DOI":"10.1210\/en.2011-2117","article-title":"Multiligand specificity and wide tissue expression of GPRC6A reveals new endocrine networks.","volume":"153","author":"Pi","year":"2012","journal-title":"Endocrinology"},{"key":"2020071612125474500_B36","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1126\/science.1371193","article-title":"Insulin secretion from pancreatic B cells caused by l-arginine-derived nitrogen oxides.","volume":"255","author":"Schmidt","year":"1992","journal-title":"Science"},{"key":"2020071612125474500_B37","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1210\/endo-124-1-134","article-title":"Stimulus-secretion coupling of arginine-induced insulin release. Uptake of metabolized and nonmetabolized cationic amino acids by pancreatic islets.","volume":"124","author":"Blachier","year":"1989","journal-title":"Endocrinology"},{"key":"2020071612125474500_B38","doi-asserted-by":"crossref","first-page":"2096","DOI":"10.1007\/s00125-012-2562-9","article-title":"Cell signalling in insulin secretion: the molecular targets of ATP, cAMP and sulfonylurea.","volume":"55","author":"Seino","year":"2012","journal-title":"Diabetologia"},{"key":"2020071612125474500_B39","doi-asserted-by":"crossref","first-page":"230","DOI":"10.3945\/jn.108.096362","article-title":"Dietary l-arginine supplementation reduces white fat gain and enhances skeletal muscle and brown fat masses in diet-induced obese rats.","volume":"139","author":"Jobgen","year":"2009","journal-title":"J Nutr"},{"key":"2020071612125474500_B40","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1093\/jn\/135.4.714","article-title":"Dietary l-arginine supplementation reduces fat mass in Zucker diabetic fatty rats.","volume":"135","author":"Fu","year":"2005","journal-title":"J Nutr"},{"key":"2020071612125474500_B41","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1007\/s00726-010-0598-z","article-title":"Beneficial effects of l-arginine on reducing obesity: potential mechanisms and important implications for human health.","volume":"39","author":"McKnight","year":"2010","journal-title":"Amino Acids"},{"key":"2020071612125474500_B42","doi-asserted-by":"crossref","first-page":"E906","DOI":"10.1152\/ajpendo.00002.2006","article-title":"Beneficial effects of a long-term oral l-arginine treatment added to a hypocaloric diet and exercise training program in obese, insulin-resistant type 2 diabetic patients.","volume":"291","author":"Lucotti","year":"2006","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2020071612125474500_B43","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1089\/met.2009.0032","article-title":"Low levels of plasma agmatine in the metabolic syndrome.","volume":"8","author":"Jo","year":"2010","journal-title":"Metab Syndr Relat Disord"},{"key":"2020071612125474500_B44","doi-asserted-by":"crossref","first-page":"2067","DOI":"10.1210\/jcem.87.5.8509","article-title":"Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency.","volume":"87","author":"Biller","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612125474500_B45","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1038\/ejcn.2010.21","article-title":"The effects of dietary protein on the somatotropic axis: a comparison of soy, gelatin, \u03b1-lactalbumin and milk.","volume":"64","author":"van Vught","year":"2010","journal-title":"Eur J Clin Nutr"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/153\/10\/4608\/10383636\/endo4608.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/153\/10\/4608\/10383636\/endo4608.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T17:43:43Z","timestamp":1714412623000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/153\/10\/4608\/2424251"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,10,1]]},"references-count":45,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2012,10,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2012-1301","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,10,1]]}}}