Activation of the extracellular calcium-sensing receptor initiates insulin secretion from human islets of Langerhans: involvement of protein kinases.
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.
Gray
Elizabeth
E
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.
Muller
Dany
D
Squires
Paul E
PE
Asare-Anane
Henry
H
Huang
Guo-Cai
GC
Amiel
Stephanie
S
Persaud
Shanta J
SJ
Jones
Peter M
PM
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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