two control mechanisms affecting protein trafficking to the plasma membrane and transporter kinetics by phosphorylation 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 the WNK3 and WNK4 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. 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 and vasopressin, can regulate NCC activity by phosphorylating conserved serine/threonine residues. NCC activity can be inhibited by thiazides, which is why this symporter is also known as the thiazide-sensitive Na+-Cl− cotransporter. Pathology Gitelman syndrome A loss of NCC function is associated with Gitelman syndrome, an autosomic recessive disease characterized by salt wasting and low blood pressure, hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria. Over a hundred different mutations in the NCC gene have been described as causing Gitelman syndrome, including nonsense, frameshift, splice site and missense 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. 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. 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. However, in some patients with Gitelman's syndrome, no mutations in the NCC gene have been found despite extensive genetic work-up. Hypertension and blood pressure NCC has also been implicated to play a role in control of blood pressure in the open population, with both common polymorphisms and rare mutations