title: Modulation of neuronal activity by phosphorylation of the K-Cl cotransporter KCC2.
abstract: The K-Cl cotransporter KCC2 establishes the low intraneuronal Cl- levels required for the hyperpolarizing inhibitory postsynaptic potentials mediated by ionotropic γ-aminobutyric acid receptors (GABAARs) and glycine receptors (GlyRs). Decreased KCC2-mediated Cl- extrusion and impaired hyperpolarizing GABAAR- and/or GlyR-mediated currents have been implicated in epilepsy, neuropathic pain, and spasticity. Recent evidence suggests that the intrinsic ion transport rate, cell surface stability, and plasmalemmal trafficking of KCC2 are rapidly and reversibly modulated by the (de)phosphorylation of critical serine, threonine, and tyrosine residues in the C terminus of this protein. Alterations in KCC2 phosphorylation have been associated with impaired KCC2 function in several neurological diseases. Targeting KCC2 phosphorylation directly or indirectly via upstream regulatory kinases might be a novel strategy to modulate GABA- and/or glycinergic signaling for therapeutic benefit.
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.|Howard Hughes Medical Institute, Department of Cardiology, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Kristopher T
authors.initials: KT
authors.lastname: Kahle
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Tarek Z
authors.initials: TZ
authors.lastname: Deeb
authors.affiliation: Department of Biosciences and Neuroscience Center, University of Helsinki, FI-00014 Helsinki, Finland.
authors.forename: Martin
authors.initials: M
authors.lastname: Puskarjov
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Liliya
authors.initials: L
authors.lastname: Silayeva
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Liang
authors.affiliation: Department of Biosciences and Neuroscience Center, University of Helsinki, FI-00014 Helsinki, Finland.
authors.forename: Kai
authors.initials: K
authors.lastname: Kaila
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA.|Department of Neuroscience, Physiology and Pharmacology, University College, London, WC1E 6BT, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Moss
mesh_terms: D000818:Animals; D006801:Humans; D008954:Models, Biological; D009422:Nervous System Diseases / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D018079:Receptors, GABA; D018009:Receptors, Glycine; D015398:Signal Transduction / Q000502:physiology; D027981:Symporters / Q000378:metabolism*; D000096922:K Cl- Cotransporters
chemical_list: D018079:Receptors, GABA; D018009:Receptors, Glycine; D027981:Symporters; D000096922:K Cl- Cotransporters