title: The extracellular calcium-sensing receptor on human beta-cells negatively modulates insulin secretion.
abstract: 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.
authors.affiliation: Endocrinology and Reproduction Research Group, School of Biomedical Sciences, King's College London, UK. paul.squires@kcl.ac.uk
authors.forename: P E
authors.initials: PE
authors.lastname: Squires
authors.forename: T E
authors.initials: TE
authors.lastname: Harris
authors.forename: S J
authors.initials: SJ
authors.lastname: Persaud
authors.forename: S B
authors.initials: SB
authors.lastname: Curtis
authors.forename: A M
authors.initials: AM
authors.lastname: Buchan
authors.forename: P M
authors.initials: PM
authors.lastname: Jones
mesh_terms: D002118:Calcium / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism / Q000502:physiology*; D010179:Pancreas / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D007328:Insulin; D012333:RNA, Messenger; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface; D000242:Cyclic AMP; D002118:Calcium