SLC12

SLC12, or the solute carrier family 12, is a family of cation–chloride cotransporters encoded by the SLC12 gene family. Members include SLC12A1 (NKCC2), SLC12A2 (NKCC1), SLC12A3 (NCC), and the K+-Cl− cotransporters SLC12A4–SLC12A7 (KCC1–KCC4). These transporters are expressed in a variety of tissues, with major roles in renal, epithelial, and nervous system function.

Functionally, the SLC12 transporters mediate electroneutral transport of sodium, potassium, and chloride ions across the plasma membrane. They contribute to transepithelial salt transport in the kidney and other epithelia, regulate intracellular chloride concentration and cell volume, and help control neuronal chloride homeostasis that influences inhibitory signaling in the brain. NKCC1 and NKCC2 are key in many secretory and absorptive processes, NCC mediates NaCl reabsorption in the distal tubule, and the KCCs extrude Cl− from cells.

Regulation and pharmacology: SLC12 transporters are regulated by WNK kinases and SPAK/OSR1 signaling pathways, and their activity is modulated by hormonal signals such as aldosterone and vasopressin. They are well known as pharmacological targets: loop diuretics inhibit NKCC1 and NKCC2, while thiazide diuretics inhibit NCC.

Clinical significance: Mutations or dysregulation of SLC12 family members are linked to renal tubulopathies such as Bartter and Gitelman syndromes, reflecting disrupted renal salt handling. Altered chloride homeostasis in the CNS, involving KCC2 and related transporters, has been implicated in neurological and developmental disorders, including epilepsy and other excitability disorders. The family remains a focus of research in electrolyte balance and neuronal signaling.