Diabetes, Vol 49, Issue 3 409-417, Copyright © 2000 by American Diabetes Association

ARTICLES

The extracellular calcium-sensing receptor on human beta-cells negatively modulates insulin secretion

PE Squires, TE Harris, SJ Persaud, SB Curtis, AM Buchan and PM Jones
Endocrinology and Reproduction Research Group, School of Biomedical Sciences, King's College London, UK. paul.squires@kcl.ac.uk

The presence and functional significance of the extracellular calcium-sensing receptor (CaR) on human pancreatic beta-cells were investigated. Reverse transcriptase-polymerase chain reaction with primers for the extracellular domain of the CaR expressed in human parathyroid-secreting cells identified a product of the expected size in human pancreatic mRNA. Immunocytochemistry using an antibody against the extracellular region of CaR showed extensive immunoreactivity in insulin- and glucagon-containing cells but not in somatostatin-containing cells. In perifusion experiments, elevations in extracellular Ca2+ produced initial transient increases in insulin secretion, followed by a concentration-dependent and prolonged, but reversible, inhibition of secretion. Microfluorometric measurements of intracellular Ca2+ ([Ca2+]i) in isolated human beta-cells demonstrated that elevations in extracellular Ca2+ (0.5-10 mmol/l) caused rapid elevations in [Ca2+]i. Increases in extracellular Ca2+ caused small increases in the cyclic AMP content of whole human islets. These studies demonstrated that human beta-cells express an extracellular CaR and that activation of the receptor inhibits basal and nutrient-stimulated insulin secretion. The transduction mechanism that mediates this inhibitory effect is unknown, but our results suggest that it is unlikely to be through the adenylate cyclase-cyclic AMP pathway or through the phospholipase C-IP3 pathway. This CaR-mediated inhibitory mechanism may be an important autoregulatory mechanism in the control of insulin secretion.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J.-C. Henquin, D. Dufrane, and M. Nenquin Nutrient Control of Insulin Secretion in Isolated Normal Human Islets Diabetes, December 1, 2006; 55(12): 3470 - 3477. [Abstract] [Full Text] [PDF]

				E. Gray, D. Muller, P. E Squires, H. Asare-Anane, G.-C. Huang, S. Amiel, S. J Persaud, and P. M Jones Activation of the extracellular calcium-sensing receptor initiates insulin secretion from human islets of Langerhans: involvement of protein kinases. J. Endocrinol., September 1, 2006; 190(3): 703 - 710. [Abstract] [Full Text] [PDF]

				Y.-C. Lu, C. Sternini, E. Rozengurt, and E. Zhukova Release of Transgenic Human Insulin from Gastric G Cells: A Novel Approach for the Amelioration of Diabetes Endocrinology, June 1, 2005; 146(6): 2610 - 2619. [Abstract] [Full Text] [PDF]

				M. Cifuentes, C. Albala, and C. Rojas Calcium-Sensing Receptor Expression in Human Adipocytes Endocrinology, May 1, 2005; 146(5): 2176 - 2179. [Abstract] [Full Text] [PDF]

				P. M. Jones, C. J. Burns, V. D. Belin, H. M. Roderigo-Milne, and S. J. Persaud The Role of Cytosolic Phospholipase A2 in Insulin Secretion Diabetes, February 1, 2004; 53(90001): S172 - 178. [Abstract] [Full Text]

				C. A. Leech and J. F. Habener Regulation of Glucagon-Like Peptide-1 Receptor and Calcium-Sensing Receptor Signaling by L-Histidine Endocrinology, November 1, 2003; 144(11): 4851 - 4858. [Abstract] [Full Text] [PDF]

				E. M. Brown and R. J. MacLeod Extracellular Calcium Sensing and Extracellular Calcium Signaling Physiol Rev, January 1, 2001; 81(1): 239 - 297. [Abstract] [Full Text] [PDF]