title: K-Cl cotransporters, cell volume homeostasis, and neurological disease.
abstract: K(+)-Cl(-) cotransporters (KCCs) were originally characterized as regulators of red blood cell (RBC) volume. Since then, four distinct KCCs have been cloned, and their importance for volume regulation has been demonstrated in other cell types. Genetic models of certain KCCs, such as KCC3, and their inhibitory WNK-STE20/SPS1-related proline/alanine-rich kinase (SPAK) serine-threonine kinases, have demonstrated the evolutionary necessity of these molecules for nervous system cell volume regulation, structure, and function, and their involvement in neurological disease. The recent characterization of a swelling-activated dephosphorylation mechanism that potently stimulates the KCCs has pinpointed a potentially druggable switch of KCC activity. An improved understanding of WNK/SPAK-mediated KCC cell volume regulation in the nervous system might reveal novel avenues for the treatment of multiple neurological diseases.
authors.affiliation: Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02114, USA; Manton Center for Orphan Disease Research, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02114, USA. Electronic address: kkahle@enders.tch.harvard.edu.
authors.forename: Kristopher T
authors.initials: KT
authors.lastname: Kahle
authors.affiliation: Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Arjun R
authors.initials: AR
authors.lastname: Khanna
authors.affiliation: Renal Division and Molecular and Vascular Medicine Division, Beth Israel Deaconess Medical Center; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Seth L
authors.initials: SL
authors.lastname: Alper
authors.affiliation: Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA.
authors.forename: Norma C
authors.initials: NC
authors.lastname: Adragna
authors.affiliation: Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA; Department of Pathology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Lauf
authors.affiliation: Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15217, USA; Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, PA 15213, USA.
authors.forename: Dandan
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: eric.delpire@vanderbilt.edu.
authors.forename: Eric
authors.initials: E
authors.lastname: Delpire
mesh_terms: D001921:Brain / Q000378:metabolism; D001929:Brain Edema / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048429:Cell Size; D006706:Homeostasis; D006801:Humans; D009422:Nervous System Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D027981:Symporters / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000096922:K Cl- Cotransporters
chemical_list: D017346:Protein Serine-Threonine Kinases; D027981:Symporters; D000096922:K Cl- Cotransporters
keywords: KCC2; KCC3; NKCC1; WNK-SPAK/OSR1; cell volume; cerebral edema