8 J. Endocrinol. Invest. 34 (Suppl. to no. 7): 8-12, 2011 ABSTRACT. Calcium sensing receptor (CaSR) is a component of the C family of the G protein-cou- pled receptors. It is ubiquitously expressed in human and mammal cells but is more expressed in parathyroid glands and kidney cells. It is lo- cated on the cell plasma membrane and senses the changes of extracellular calcium concentra- tions. Thus, it may modify cell functions accord- ing to serum calcium levels. CaSR has a key role in calcium homeostasis because it allows para- thyroid glands and kidney to regulate PTH se- cretion and calcium reabsorption in order to keep serum calcium concentration within the normal range. CaSR appears as an important player in the regulation of renal calcium handling and body calcium metabolism. Thus, CaSR may protect human tissues against calcium excess. In kidneys, its protective effect includes the stim- ulation of diuresis and phosphate retention, along with the potential prevention of calcium precipitation and deposition in kidney tubules and interstitium. [J. Endocrinol. Invest. 34 (Suppl. to no. 7): 8-12, 2011] © 2011, Editrice Kurtis INTRODUCTION Calcium sensing receptor (CaSR) is a component of the family C of the G protein-coupled receptors (GPCR). It is ubiquitously expressed in human and mammal cells, but is more abundantly expressed in parathyroid gland and kidney cells (1). It is locat- ed on the cell plasma membrane and senses the changes of extracellular calcium concentrations. Thus, it may modify cell function according to the serum calcium level (2-4) and regulate the function of parathyroid glands and kidney according to the circulating concentrations of calcium. CaSR molecule is a dimer sited on the cell plasma membrane. Each monomer consists of a wide ex- tracellular domain (612 amino acids) able to bind calcium ions with its multiple negative charges, a 7-membrane-spanning transmembrane domain (250 amino acids) and a shorter intracellular tail (216 amino acids) enabling CaSR to generate multiple intracellular transduction signals by activating G protein family members (G i ,G q ,G 11 or G 12 ) (5). G i protein inhibits adenilate-cyclase, while G q ,G 11 , and G 12 proteins stimulate phospholipase C, A2 or D (6) to activate their signaling pathways. CaSR in- tracellular domain may also interact with filamin A, a cytoskeletal scaffolding protein necessary for G q protein and Rho signaling (7). Furthermore, it may activate mitogen-activated-posphorilase-kinase (MAPK) pathways, thus potentially influencing gene transcription and cell proliferation (5, 6). CaSR has a key role in calcium homeostasis be- cause it allows parathyroid glands and kidney to regulate PTH secretion and calcium reabsorption in order to keep serum calcium concentration with- in the normal range. CaSR is also expressed in bone and intestinal cells where it controls gastric acid se- cretion, enteral fluid secretion, and bone resorp- tion (8, 9). Its contribution to intestinal calcium ab- sorption is yet uncertain, whereas its function in bone development and remodeling may be exert- ed in a complex way as shown in experiments of selective silencing of its expression (10, 11). In kidney, CaSR has been detected in all nephron segments. It exerts an inhibitory activity on the re- absorption of calcium, potassium, sodium, and wa- ter according to the peculiar function of the differ- ent tubular tracts. In its inhibitory effects CaSR mod- ulates the activity of the signaling pathways used by tubular cells to activate electrolyte or water re- absorption. On the contrary, in proximal tubule Key-words: Calcification, calcium-sensing receptor, calcium transport, ion transport, kidney stones. Correspondence: G. Vezzoli, MD, Unità di Nefrologia e Dialisi, IRCCS Os- pedale San Raffaele, via Olgettina 60, 20132, Milano, Italy. E-mail: vezzoli.giuseppe@hsr.it Calcium sensing receptor and renal mineral ion transport F. Rainone 1 , T. Arcidiacono 1 , A. Terranegra 2 , A. Aloia 2 , E. Dogliotti 2 , A. Mingione 2 , D. Spotti 1 , C.M. Francucci 3 , L. Soldati 2 , and G. Vezzoli 1 1 Nephrology and Dialysis Unit, Vita Salute University, San Raffaele Scientific Institute; 2 Department of Medicine Surgery and Dentistry, IRCCS Policlinico San Paolo, Milan; 3 Division of Endocrinology, Department of Internal Medicine, Polytechnic University of Marche, Ancona, Italy © 2011, Editrice Kurtis FOR PERSONAL USE ONLY