Localization and function of the renal calcium-sensing receptor

The ability to monitor changes in the ionic composition of the extracellular environment is a crucial feature that has evolved in all living organisms. The cloning and characterization of the extracellular calcium-sensing receptor (CaSR) from the mammalian parathyroid gland in the early 1990s provided the first description of a cellular, ion-sensing mechanism. This finding demonstrated how cells can detect small, physiological variations in free ionized calcium (Ca 2+) in the extracellular fluid and subsequently evoke an appropriate biological response by altering the secretion of parathyroid hormone (PTH) that acts on PTH receptors expressed in target tissues, including the kidney, intestine, and bone. Aberrant Ca 2+ sensing by the parathyroid glands, as a result of altered CaSR expression or function, is associated with impaired divalent cation homeostasis. CaSR activators that mimic the effects of Ca 2+ (calcimimetics) have been designed to treat hyperparathyroidism, and CaSR antagonists (calcilytics) are in development for the treatment of hypercalciuric disorders. The kidney expresses a CaSR that might directly contribute to the regulation of many aspects of renal function in a PTH-independent manner. This Review discusses the roles of the renal CaSR and the potential impact of pharmacological modulation of the CaSR on renal function

Regulation of magnesium reabsorption in DCT.

Contains fulltext : 81724.pdf (publisher's version ) (Closed access)The distal convoluted tubule (DCT) is the shortest segment of the nephron and consists of an early (DCT1) and late part (DCT2). Here, several transport proteins, like the thiazide-sensitive NaCl cotransporter (NCC) and the epithelial magnesium (Mg(2+)) channel (TRPM6), are exclusively expressed. This makes the DCT the major site of active transcellular Mg(2+) reabsorption determining the final excretion in the urine. Following the Mg(2+) influx via the apically localized TRPM6, intracellular Mg(2+) diffuses to the basolateral membrane where it is extruded to the blood compartment via still-unidentified Mg(2+) transporters. Recent years have witnessed multiple breakthroughs in the field of transcellular Mg(2+) reabsorption. Epidermal growth factor and estrogen were identified as magnesiotropic hormones by their effect on TRPM6 activity. Intracellularly, receptor of activated protein kinase C 1 and adenosine triphosphate were shown to inhibit TRPM6 activity through its alpha-kinase domain. Furthermore, dysregulation or malfunction of transcellular Mg(2+) reabsorption in DCT has been associated with renal Mg(2+) wasting. Mutations in TRPM6 are responsible for hypomagnesemia with secondary hypocalcemia. A defect in the gamma-subunit of the Na(+)/K(+)-adenosine triphosphatase causes isolated dominant hypomagnesemia resulting from renal Mg(2+) wasting. Moreover, in Gitelman's syndrome, mutations in NCC also result in impaired transcellular Mg(2+) reabsorption in DCT. This review highlights our recently obtained knowledge concerning the molecular regulation of transcellular Mg(2+) reabsorption