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

Abstract

The balance between the concentrations of free ionized Ca 2؉ 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 Ca 2؉ saturation in an alkaline environment such as the pancreatic juice is not known. Because of the tight cause-effect relationship between Ca 2؉ concentration and lithogenicity, and because hypercalcemia is proposed as an etiologic factor for several pancreatic diseases, we have investigated whether pancreatic tissues express a Ca 2؉ -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 Ca 2؉ concentration was measured in isolated acinar cells and interlobular ducts, show that both cell types are responsive to the CaR agonist gadolinium (Gd 3؉ ) and to changes in extracellular Ca 2؉ concentration. We also assessed the effects of CaR stimulation on physiological HCO 3 ؊ secretion from ducts by making measurements of intracellular pH. Luminal Gd 3؉ is a potent stimulus for HCO 3 ؊ secretion, being equally as effective as raising intracellular cAMP with forskolin. These results suggest that the CaR in the exocrine pancreas monitors the Ca 2؉ concentration in the pancreatic juice, and might therefore be involved in regulating the level of Ca 2؉ 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.

L-Amino acid sensing by the calcium-sensing receptor: a general mechanism for coupling protein and calcium metabolism?

“…However, its widespread expression, throughout the body, implies expanded biological roles that are unrelated to its major role in calcium homeostasis. Thus, the CaR is also expressed in the brain (in nerve and glial cells; Chattopadhyay et al, 1997Chattopadhyay et al, , 1998bRuat et al, 1995), skin (Bikle et al, 1996;Oda et al, 1998), the gastrointestinal tract including the stomach (Cheng et al, 1998;Ray et al, 1997;Rutten et al, 1999), small and large intestine (Chattopadhyay et al, 1998a;Gama et al, 1997), pancreas (Bruce et al, 1999) and liver (Canaff et al, 2001) as well as the placenta (Bradbury et al, 1998;Kovacs et al, 1998), and bone marrow (House et al, 1997).…”

Apical Localization of a Functional TRPC3/TRPC6-Ca2+-Signaling Complex in Polarized Epithelial Cells

“…Re-absorption of Ca 2ϩ can also have an impact on pathological conditions such as sialoliths that are formed when salivary [Ca 2ϩ ] is increased (40). Most interestingly, it has been suggested that Ca 2ϩ is reabsorbed from the lumen of pancreatic ducts and that failure of this mechanism could lead to formation of pancreatic stones or pancreatitis (41). Thus, determining the exact localization of TRPC channels in different epithelial tissues and identifying the Ca 2ϩ -signaling system they are coupled to will provide a better understanding of the physiological function and regulation of these channels.…”

Chloride-Dependent Intracellular pH Regulation via Extracellular Calcium-Sensing Receptor in the Medullary Thick Ascending Limb of the Mouse Kidney

“…In parathyroid glands, the CaSR activates phospholipase C (PLC), resulting in the inhibition of parathyroid hormone (PTH) secretion . The CaSR is also expressed in multiple tissues including C cells in the thyroid (Garrett et al 1995), renal tubules, gastric mucous epithelial cells (Rutten et al 1999), ileum (Ruat et al 1995), bone, bone marrow cells (House et al 1997), pituitary (Ruat et al 1995), nerve terminals in brain (Ruat et al 1995), keratinocytes in skin (Bikle et al 1996), islet B-cells in pancreas (Bruce et al 1999), lung (Ruat et al 1995), and heart .…”