The SLC12 family of chloride transporters contribute to ion fluxes across a variety of tissues, particularly in the kidney and choroid plexus of the brain. Within this family, further subfamilies are identifiable: NKCC1, NKCC2 and NCC constitute a group of therapeutically-relevant transporters, targets for loop and thiazide diuretics. These 12 TM proteins exhibit cytoplasmic termini and an extended extracellular loop at TM7/8 and are kidney-specific (NKCC2 and NCC) or show a more widespread distribution (NKCC1). A second family, the K-Cl co-transporters are also 12 TM domain proteins with cytoplasmic termini, but with an extended extracellular loop at TM 5/6. CCC6 exhibits structural similarities with the K-Cl co-transporters, while CCC9 is divergent, with 11 TM domains and a cytoplasmic N-terminus and extracellular C-terminus.

DIOA is able to differentiate KCC isoforms from NKCC and NCC transporters, but also inhibits CFTR [4].

* Key recommended reading is highlighted with an asterisk

* Arroyo JP, Kahle KT, Gamba G. (2013) The SLC12 family of electroneutral cation-coupled chloride cotransporters. Mol Aspects Med, 34 (2-3): 288-98. [PMID:23506871]

* Bachmann S, Mutig K. (2017) Regulation of renal Na-(K)-Cl cotransporters by vasopressin. Pflugers Arch, 469 (7-8): 889-897. [PMID:28577072]

* Bazúa-Valenti S, Castañeda-Bueno M, Gamba G. (2016) Physiological role of SLC12 family members in the kidney. Am J Physiol Renal Physiol, 311 (1): F131-44. [PMID:27097893]

Castrop H, Schießl IM. (2014) Physiology and pathophysiology of the renal Na-K-2Cl cotransporter (NKCC2). Am J Physiol Renal Physiol, 307 (9): F991-F1002. [PMID:25186299]

Castrop H, Schnermann J. (2008) Isoforms of renal Na-K-2Cl cotransporter NKCC2: expression and functional significance. Am J Physiol Renal Physiol, 295 (4): F859-66. [PMID:18495801]

Gagnon KB, Delpire E. (2013) Physiology of SLC12 transporters: lessons from inherited human genetic mutations and genetically engineered mouse knockouts. Am J Physiol, Cell Physiol, 304 (8): C693-714. [PMID:23325410]

Gamba G, Friedman PA. (2009) Thick ascending limb: the Na(+):K (+):2Cl (-) co-transporter, NKCC2, and the calcium-sensing receptor, CaSR. Pflugers Arch, 458 (1): 61-76. [PMID:18982348]

Hebert SC, Mount DB, Gamba G. (2004) Molecular physiology of cation-coupled Cl- cotransport: the SLC12 family. Pflugers Arch, 447 (5): 580-93. [PMID:12739168]

* Huang X, Dorhout Mees E, Vos P, Hamza S, Braam B. (2016) Everything we always wanted to know about furosemide but were afraid to ask. Am J Physiol Renal Physiol, 310 (10): F958-71. [PMID:26911852]

* Kahle KT, Khanna AR, Alper SL, Adragna NC, Lauf PK, Sun D, Delpire E. (2015) K-Cl cotransporters, cell volume homeostasis, and neurological disease. Trends Mol Med, 21 (8): 513-23. [PMID:26142773]

Kahle KT, Rinehart J, Lifton RP. (2010) Phosphoregulation of the Na-K-2Cl and K-Cl cotransporters by the WNK kinases. Biochim Biophys Acta, 1802 (12): 1150-8. [PMID:20637866]

Kahle KT, Staley KJ, Nahed BV, Gamba G, Hebert SC, Lifton RP, Mount DB. (2008) Roles of the cation-chloride cotransporters in neurological disease. Nat Clin Pract Neurol, 4 (9): 490-503. [PMID:18769373]

Lang F, Vallon V, Knipper M, Wangemann P. (2007) Functional significance of channels and transporters expressed in the inner ear and kidney. Am J Physiol, Cell Physiol, 293 (4): C1187-208. [PMID:17670895]

Lionetto MG, Schettino T. (2006) The Na+-K+-2Cl- cotransporter and the osmotic stress response in a model salt transport epithelium. Acta Physiol (Oxf), 187 (1-2): 115-24. [PMID:16734748]

Löscher W, Puskarjov M, Kaila K. (2013) Cation-chloride cotransporters NKCC1 and KCC2 as potential targets for novel antiepileptic and antiepileptogenic treatments. Neuropharmacology, 69: 62-74. [PMID:22705273]

Markadieu N, Delpire E. (2014) Physiology and pathophysiology of SLC12A1/2 transporters. Pflugers Arch, 466 (1): 91-105. [PMID:24097229]

* Martín-Aragón Baudel MA, Poole AV, Darlison MG. (2017) Chloride co-transporters as possible therapeutic targets for stroke. J Neurochem, 140 (2): 195-209. [PMID:27861901]

Moes AD, van der Lubbe N, Zietse R, Loffing J, Hoorn EJ. (2014) The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation. Pflugers Arch, 466 (1): 107-18. [PMID:24310820]

Wagner CA, Devuyst O, Bourgeois S, Mohebbi N. (2009) Regulated acid-base transport in the collecting duct. Pflugers Arch, 458 (1): 137-56. [PMID:19277700]

1. Delpire E, Days E, Lewis LM, Mi D, Kim K, Lindsley CW, Weaver CD. (2009) Small-molecule screen identifies inhibitors of the neuronal K-Cl cotransporter KCC2. Proc Natl Acad Sci USA, 106 (13): 5383-8. [PMID:19279215]

2. Grozio A, Mills KF, Yoshino J, Bruzzone S, Sociali G, Tokizane K, Lei HC, Cunningham R, Sasaki Y, Migaud ME et al.. (2019) Slc12a8 is a nicotinamide mononucleotide transporter. Nat Metab, 1 (1): 47-57. DOI: 10.1038/s42255-018-0009-4 [PMID:31131364]

3. Hannaert P, Alvarez-Guerra M, Pirot D, Nazaret C, Garay RP. (2002) Rat NKCC2/NKCC1 cotransporter selectivity for loop diuretic drugs. Naunyn Schmiedebergs Arch Pharmacol, 365 (3): 193-9. [PMID:11882915]

4. Ito Y, Aoyama M, Yamada N, Mizuno Y, Kume H, Yamaki K. (2001) [(Dihydroindenyl)oxy]alkonic acid inhibits the cystic fibrosis transmembrane conductance regulator. Eur J Pharmacol, 426 (3): 175-8. [PMID:11527541]