Thesodium-chloride symporter (also known asNa+-Cl− cotransporter,NCC orNCCT, or as thethiazide-sensitive Na+-Cl− cotransporter orTSC) is acotransporter in thekidney which has the function of reabsorbingsodium andchlorideions from thetubular fluid into the cells of thedistal convoluted tubule of thenephron. It is a member of theSLC12 cotransporter family of electroneutral cation-coupled chloride cotransporters. In humans, it is encoded by theSLC12A3gene (solute carrier family 12 member 3) located in16q13.[5]
A loss of NCC function causesGitelman syndrome, an autosomic recessive disease characterized by salt wasting and low blood pressure, hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria.[6] Over a hundred different mutations in the NCC gene have been identified.
N-glycosylation occurs in two sites in a long extracellular loop connecting two transmembrane domains within the hydrophobic core. Thisposttranslational modification is necessary for proper folding and transport of the protein to theplasma membrane.[7]
Because NCC is located at theapical membrane of the distal convoluted tubule of the nephron, it faces thelumen of the tubule and is in contact with the tubular fluid. Using thesodium gradient across the apical membrane of the cells in distal convoluted tubule, the sodium-chloride symporter transports Na+ and Cl− from the tubular fluid into these cells. Afterward, the Na+ is pumped out of the cell and into the bloodstream by the Na+-K+ ATPase located at thebasal membrane and the Cl− leaves the cells through the basolateralchloride channel ClC-Kb. The sodium-chloride symporter accounts for the absorption of 5% of the salt filtered at theglomerulus. NCC activity is known to have two control mechanisms affecting protein trafficking to the plasma membrane and transporter kinetics byphosphorylation and de-phosphorylation of conserved serine/threonine residues.
As NCC has to be at the plasma membrane to function, its activity can be regulated by increasing or decreasing the amount of protein at the plasma membrane. Some NCC modulators, such as theWNK3 andWNK4 kinases may regulate the amount of NCC at the cell surface by inducing the insertion or removal, respectively, of the protein from the plasma membrane.[8][9]
Furthermore, many residues of NCC can be phosphorylated or dephosphorylated to activate or inhibit NCC uptake of Na+ and Cl−. Other NCC modulators, including intracellular chloride depletion,angiotensin II,aldosterone andvasopressin, can regulate NCC activity by phosphorylating conserved serine/threonine residues.[10][11][12] NCC activity can be inhibited bythiazides, which is why this symporter is also known as the thiazide-sensitive Na+-Cl− cotransporter.[5]
A loss of NCC function is associated withGitelman syndrome, an autosomic recessive disease characterized by salt wasting and low blood pressure, hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria.[6]
Over a hundred different mutations in the NCC gene have been described as causing Gitelman syndrome, includingnonsense,frameshift,splice site andmissense mutations. Two different types of mutations exist within the group of missense mutations causing loss of NCC function. Type I mutations cause a complete loss of NCC function, in which the synthesized protein is not properly glycosylated. NCC protein harboring type I mutations is retained in the endoplasmic reticulum and cannot be trafficked to the cell surface.[13] Type II mutations cause a partial loss of NCC function in which the cotransporter is trafficked to the cell surface but has an impaired insertion in the plasma membrane. NCC harboring type II mutations have normal kinetic properties but are present in lower amounts at the cell surface, resulting in a decreased uptake of sodium and chloride.[14] NCC harboring type II mutations is still under control of its modulators and can still increase or decrease its activity in response to stimuli, whereas type I mutations cause a complete loss of function and regulation of the cotransporter.[15] However, in some patients with Gitelman's syndrome, no mutations in the NCC gene have been found despite extensive genetic work-up.
NCC has also been implicated to play a role in control ofblood pressure in the open population, with both common polymorphisms and rare mutations altering NCC function, renal salt reabsorption and, presumably, blood pressure. Individuals with rare mutations in genes responsible for salt control in the kidney, including NCC, have been found to have a lower blood pressure thancontrols.[16] NCC harboring these mutations has a lower function thanwild-type cotransporter although some mutations found in individuals in the open population seem to be less deleterious to cotransporter function than mutations in individuals with Gitelman's syndrome.[15]
Furthermore, heterozygouscarriers of mutations causing Gitelman syndrome (i.e. individuals who have a mutation in one of the twoalleles and do not have the disease) have a lower blood pressure than non-carriers in the same family.[17]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
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^Sabath E, Meade P, Berkman J, de los Heros P, Moreno E, Bobadilla NA, et al. (August 2004). "Pathophysiology of functional mutations of the thiazide-sensitive Na-Cl cotransporter in Gitelman disease".American Journal of Physiology. Renal Physiology.287 (2):F195 –F203.doi:10.1152/ajprenal.00044.2004.PMID15068971.
^abAcuña R, Martínez-de-la-Maza L, Ponce-Coria J, Vázquez N, Ortal-Vite P, Pacheco-Alvarez D, et al. (March 2011). "Rare mutations in SLC12A1 and SLC12A3 protect against hypertension by reducing the activity of renal salt cotransporters".Journal of Hypertension.29 (3):475–483.doi:10.1097/HJH.0b013e328341d0fd.PMID21157372.S2CID205630437.
^Fava C, Montagnana M, Rosberg L, Burri P, Almgren P, Jönsson A, et al. (February 2008). "Subjects heterozygous for genetic loss of function of the thiazide-sensitive cotransporter have reduced blood pressure".Human Molecular Genetics.17 (3):413–418.doi:10.1093/hmg/ddm318.PMID17981812.
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