title: Activation of the extracellular calcium-sensing receptor initiates insulin secretion from human islets of Langerhans: involvement of protein kinases.
abstract: The extracellular calcium-sensing receptor (CaR) is usually associated with systemic Ca(2+) homeostasis, but the CaR is also expressed in many other tissues, including pancreatic islets of Langerhans. In the present study, we have used human islets and an insulin-secreting cell line (MIN6) to investigate the effects of CaR activation using the calcimimetic R-568, a CaR agonist that activates the CaR at physiological concentrations of extracellular Ca(2+). CaR activation initiated a marked but transient insulin secretory response from both human islets and MIN6 cells at a sub-stimulatory concentration of glucose, and further enhanced glucose-induced insulin secretion. CaR-induced insulin secretion was reduced by inhibitors of phospholipase C or calcium-calmodulin-dependent kinases, but not by a protein kinase C inhibitor. CaR activation was also associated with an activation of p42/44 mitogen-activated protein kinases (MAPK), and CaR-induced insulin secretion was reduced by an inhibitor of p42/44 MAPK activation. We suggest that the beta-cell CaR is activated by divalent cations co-released with insulin, and that this may be an important mechanism of intra-islet communication between beta-cells.
authors.affiliation: Beta Cell Development and Function Group, Division of Reproduction and Endocrinology, School of Biomedical and Health Sciences, King's College London, Hodgkin Building HB2.10N, Guy's Campus, London SE1 9UL, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gray
authors.forename: Dany
authors.initials: D
authors.lastname: Muller
authors.forename: Paul E
authors.initials: PE
authors.lastname: Squires
authors.forename: Henry
authors.initials: H
authors.lastname: Asare-Anane
authors.forename: Guo-Cai
authors.initials: GC
authors.lastname: Huang
authors.forename: Stephanie
authors.initials: S
authors.lastname: Amiel
authors.forename: Shanta J
authors.initials: SJ
authors.lastname: Persaud
authors.forename: Peter M
authors.initials: PM
authors.lastname: Jones
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002227:Carbazoles / Q000494:pharmacology; D002450:Cell Communication; D002460:Cell Line; D002478:Cells, Cultured; D004963:Estrenes / Q000494:pharmacology; D045604:Extracellular Fluid / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D010627:Phenethylamines; D011437:Propylamines; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D011760:Pyrrolidinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019311:Staurosporine / Q000494:pharmacology; D013268:Stimulation, Chemical; D013449:Sulfonamides / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors; D000096926:Benzenesulfonamides
chemical_list: D000814:Aniline Compounds; D000911:Antibodies, Monoclonal; D001596:Benzylamines; D002118:Calcium; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002227:Carbazoles; D004963:Estrenes; D005419:Flavonoids; D005947:Glucose; D007211:Indoles; D007328:Insulin; D020928:Mitogen-Activated Protein Kinases; D010627:Phenethylamines; D011437:Propylamines; D011493:Protein Kinase C; D011494:Protein Kinases; D011760:Pyrrolidinones; D012333:RNA, Messenger; D044169:Receptors, Calcium-Sensing; D019311:Staurosporine; D013449:Sulfonamides; D010738:Type C Phospholipases; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C081021:Go 6976; C072105:KN 93; D000096926:Benzenesulfonamides; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one