K-Cl cotransporters, cell volume homeostasis, and neurological disease

Kristopher T Kahle; Arjun R Khanna; Seth L Alper; Norma C Adragna; Peter K Lauf; Dandan Sun; Eric Delpire

doi:10.1016/j.molmed.2015.05.008

K-Cl cotransporters, cell volume homeostasis, and neurological disease

Trends Mol Med. 2015 Aug;21(8):513-23. doi: 10.1016/j.molmed.2015.05.008. Epub 2015 Jul 1.

Authors

Kristopher T Kahle¹, Arjun R Khanna², Seth L Alper³, Norma C Adragna⁴, Peter K Lauf⁵, Dandan Sun⁶, Eric Delpire⁷

Affiliations

¹ 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.
² Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02114, USA.
³ Renal Division and Molecular and Vascular Medicine Division, Beth Israel Deaconess Medical Center; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
⁴ Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA.
⁵ 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.
⁶ 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.
⁷ Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: eric.delpire@vanderbilt.edu.

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.

Keywords: KCC2; KCC3; NKCC1; WNK-SPAK/OSR1; cell volume; cerebral edema.

Publication types

Review

MeSH terms

Brain / metabolism
Brain Edema / genetics
Brain Edema / metabolism
Brain Edema / pathology
Cell Size
Homeostasis
Humans
K Cl- Cotransporters
Nervous System Diseases / genetics
Nervous System Diseases / metabolism*
Nervous System Diseases / pathology*
Protein Serine-Threonine Kinases / metabolism
Signal Transduction
Symporters / chemistry
Symporters / genetics
Symporters / metabolism*

Substances

Symporters
Protein Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding