NaClKotransporter

NaClKotransporter, often abbreviated NKCC, refers to a family of cation-chloride cotransporters that mediate the electroneutral co-transport of sodium, potassium, and chloride ions across the cell membrane. There are two main isoforms: NKCC1 (SLC12A2) and NKCC2 (SLC12A1). NKCC1 is widely expressed in many tissues, including epithelia throughout the body, the brain, and the inner ear, whereas NKCC2 is predominantly found in the apical membranes of cells in the thick ascending limb of the loop of Henle in the kidney.

The transport cycle moves 1 Na+, 1 K+, and 2 Cl− into the cell, driven by the sodium gradient maintained by the basolateral Na+/K+-ATPase. This makes the process electroneutral. The NKCCs play essential roles in ion homeostasis, volume regulation, and transepithelial transport. In the kidney, NKCC2 reabsorbs NaCl from the filtrate in the thick ascending limb, contributing to the generation of the medullary osmotic gradient and to overall Na+ balance. NKCC1 participates in intracellular chloride accumulation, cell volume control, and ion transport in various epithelia, including the choroid plexus and inner ear.

Regulation of NKCC activity occurs largely through phosphorylation by the WNK-SPAK/OSR1 kinase cascade, which increases transporter activity in response to cellular signals such as changes in volume and osmolarity. Pharmacologically, NKCC2 is the target of loop diuretics (e.g., furosemide, bumetanide), which inhibit sodium, potassium, and chloride reabsorption in the kidney to promote diuresis. Mutations in NKCC genes are linked to human disease, including Bartter syndrome type I from NKCC2 defects, and rare disorders associated with NKCC1 dysfunction.