Review The SLC12 family of electroneutral cation-coupled chloride cotransporters q Juan Pablo Arroyo a , Kristopher T. Kahle b , Gerardo Gamba a,⇑ a Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, and Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico b Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, USA Guest Editor Matthias A. Hediger Transporters in health and disease (SLC series) article info Article history: Received 16 January 2012 Accepted 9 April 2012 Keywords: Diuretics Hypertension Epilepsy WNK Psoriasis SLC12 abstract The SLC12 family encodes electroneutral cation-coupled chloride cotransporters that are critical for several physiological processes including cell volume regulation, modulation of intraneuronal chloride concentration, transepithelial ion movement, and blood pressure regulation. Members of this family are the targets of the most commonly used diuretic drugs, have been shown to be the causative genes for inherited disease such as Gitelman, Bartter and Andermann syndromes, and potentially play a role in polygenic complex dis- eases like arterial hypertension, epilepsy, osteoporosis, and cancer. Ó 2012 Elsevier Ltd. All rights reserved. Contents 1. Introduction ............................................................................................ 289 2. The Na + –(K + )–Cl À cotransporters: SLC12A1 to SLC12A3 ......................................................... 289 2.1. Slc12a1 – NKCC2 ................................................................................... 289 2.2. Slc12a2 – NKCC1 ................................................................................... 291 2.3. Slc12a3 – NCC ..................................................................................... 293 3. The K + :Cl À Cotransporters: SLC12A4 to SLC12A7 ............................................................... 294 3.1. Slc12a4 – KCC1 .................................................................................... 294 3.2. Slc12a5 – KCC2 .................................................................................... 294 3.3. Slc12a6 – KCC3 .................................................................................... 295 3.4. Slc12a7 – KCC4 .................................................................................... 296 4. The orphan members: SLC12A8 and SLC12A9 ................................................................. 296 5. Concluding comments .................................................................................... 296 Conflict of interest ....................................................................................... 296 Acknowledgments ....................................................................................... 296 References ............................................................................................. 297 0098-2997/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mam.2012.05.002 q Publication in part sponsored by the Swiss National Science Foundation through the National Center of Competence in Research (NCCR) TransCure, University of Bern, Switzerland; Director Matthias A. Hediger; Web: http://www.transcure.ch. ⇑ Corresponding author. Address: Molecular Physiology Unit, Vasco de Quiroga No. 15, Tlalpan 14000, Mexico City, Mexico. Tel.: +52 55 5513 38 68; fax: +52 55 5655 03 82. E-mail address: gamba@biomedicas.unam.mx (G. Gamba). Molecular Aspects of Medicine 34 (2013) 288–298 Contents lists available at SciVerse ScienceDirect Molecular Aspects of Medicine journal homepage: www.elsevier.com/locate/mam