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J Biol Chem, Vol. 274, Issue 29, 20561-20568, July 16, 1999

Molecular and Functional Identification of a Ca²⁺ (Polyvalent Cation)-sensing Receptor in Rat Pancreas

From the School of Biological Sciences, G38 Stopford Building, Oxford Road, Manchester M13 9PT, United Kingdom

The balance between the concentrations of free ionized Ca²⁺ and bicarbonate in pancreatic juice is of critical importance in preventing the formation of calcium carbonate stones. How the pancreas regulates the ionic composition and the level of Ca²⁺ saturation in an alkaline environment such as the pancreatic juice is not known. Because of the tight cause-effect relationship between Ca²⁺ concentration and lithogenicity, and because hypercalcemia is proposed as an etiologic factor for several pancreatic diseases, we have investigated whether pancreatic tissues express a Ca²⁺-sensing receptor (CaR) similar to that recently identified in parathyroid tissue. Using reverse transcriptase-polymerase chain reaction and immunofluorescence microscopy, we demonstrate the presence of a CaR-like molecule in rat pancreatic acinar cells, pancreatic ducts, and islets of Langerhans. Functional studies, in which intracellular free Ca²⁺ concentration was measured in isolated acinar cells and interlobular ducts, show that both cell types are responsive to the CaR agonist gadolinium (Gd³⁺) and to changes in extracellular Ca²⁺ concentration. We also assessed the effects of CaR stimulation on physiological HCO₃ secretion from ducts by making measurements of intracellular pH. Luminal Gd³⁺ is a potent stimulus for HCO₃ secretion, being equally as effective as raising intracellular cAMP with forskolin. These results suggest that the CaR in the exocrine pancreas monitors the Ca²⁺ concentration in the pancreatic juice, and might therefore be involved in regulating the level of Ca²⁺ in the lumen, both under basal conditions and during hormonal stimulation. The failure of this mechanism might lead to pancreatic stone formation and even to pancreatitis.

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