Modulation of neuronal activity by phosphorylation of the K-Cl cotransporter KCC2. 2013

Kristopher T Kahle, and Tarek Z Deeb, and Martin Puskarjov, and Liliya Silayeva, and Bo Liang, and Kai Kaila, and Stephen J Moss
Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

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.

UI MeSH Term Description Entries
D008954 Models, Biological Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment. Biological Model,Biological Models,Model, Biological,Models, Biologic,Biologic Model,Biologic Models,Model, Biologic
D009422 Nervous System Diseases Diseases of the central and peripheral nervous system. This includes disorders of the brain, spinal cord, cranial nerves, peripheral nerves, nerve roots, autonomic nervous system, neuromuscular junction, and muscle. Neurologic Disorders,Nervous System Disorders,Neurological Disorders,Disease, Nervous System,Diseases, Nervous System,Disorder, Nervous System,Disorder, Neurologic,Disorder, Neurological,Disorders, Nervous System,Disorders, Neurologic,Disorders, Neurological,Nervous System Disease,Nervous System Disorder,Neurologic Disorder,Neurological Disorder
D009474 Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM. Nerve Cells,Cell, Nerve,Cells, Nerve,Nerve Cell,Neuron
D010766 Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Phosphorylations
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000096922 K Cl- Cotransporters A subclass of symporters that specifically transport POTASSIUM and CHLORIDE ions across cellular membranes. Potassium chloride cotransporters play roles in regulating cell volume and intracellular chloride concentration. Electroneutral Potassium-Chloride Co-transporter 3,Electroneutral Potassium-Chloride Cotransporter 3,K Cl- Co-transporters,K(+), Cl(-)-Co-transporters,K(+), Cl(-)-Cotransporters,K-Cl Co-transporter,K-Cl Co-transporter 3,K-Cl Cotransporter,K-Cl Cotransporter 3,KCC2 Co-transporter,KCC2 Cotransporter,KCC3 Co-transporter,KCC3 Cotransporter,KCC4 Co-transporter,KCC4 Cotransporter,Potassium-Chloride Co-transporter 2,Potassium-Chloride Co-transporter 4,Potassium-Chloride Co-transporters,Potassium-Chloride Cotransporter 2,Potassium-Chloride Cotransporter 4,Potassium-Chloride Cotransporters,Potassium-Chloride Symporters,SLC12A5 Protein,SLC12A6 Protein,SLC12A7 Protein,Solute Carrier Family 12 Member 5,Solute Carrier Family 12 Member 6,Solute carrier family 12 member 7,Cl- Co-transporters, K,Co-transporter 2, Potassium-Chloride,Co-transporter 3, K-Cl,Co-transporter 4, Potassium-Chloride,Co-transporter, K-Cl,Co-transporter, KCC2,Co-transporter, KCC3,Co-transporter, KCC4,Co-transporters, K Cl-,Co-transporters, Potassium-Chloride,Cotransporter, K-Cl,Cotransporter, KCC2,Cotransporter, KCC3,Cotransporter, KCC4,Cotransporters, K Cl-,Cotransporters, Potassium-Chloride,Electroneutral Potassium Chloride Co transporter 3,Electroneutral Potassium Chloride Cotransporter 3,K Cl Co transporter,K Cl Co transporter 3,K Cl Co transporters,K Cl Cotransporter,K Cl Cotransporter 3,K Cl Cotransporters,KCC2 Co transporter,KCC3 Co transporter,KCC4 Co transporter,Potassium Chloride Co transporter 2,Potassium Chloride Co transporter 4,Potassium Chloride Co transporters,Potassium Chloride Cotransporter 2,Potassium Chloride Cotransporter 4,Potassium Chloride Cotransporters,Potassium Chloride Symporters,Protein, SLC12A5,Protein, SLC12A6,Protein, SLC12A7
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D018009 Receptors, Glycine Cell surface receptors that bind GLYCINE with high affinity and trigger intracellular changes which influence the behavior of cells. Glycine receptors in the CENTRAL NERVOUS SYSTEM have an intrinsic chloride channel. GlyA receptor is sensitive to STRYCHNINE and localized in the post-synaptic membrane of inhibitory glycinergic neurons. GlyB receptor is insensitive to strychnine and associated with the excitatory NMDA receptor. Excitatory Glycine Receptors,GlyA Receptors,GlyB Receptors,Glycine A Receptors,Glycine B Receptors,Glycine Receptor alpha1,Glycine Receptors,Inhibitory Glycine Receptor,SIG Receptor,Strychnine-Insensitive Glycine Receptor,Strychnine-Sensitive Glycine Receptor,Glycine Receptor,Glycine Receptor, Inhibitory,Glycine Receptor, Strychnine-Insensitive,Glycine Receptor, Strychnine-Sensitive,Receptor, Glycine,Receptor, Inhibitory Glycine,Receptor, SIG,Receptor, Strychnine-Insensitive Glycine,Receptor, Strychnine-Sensitive Glycine,Receptors, GlyB,Strychnine Insensitive Glycine Receptor,Strychnine Sensitive Glycine Receptor
D018079 Receptors, GABA Cell-surface proteins that bind GAMMA-AMINOBUTYRIC ACID with high affinity and trigger changes that influence the behavior of cells. GABA-A receptors control chloride channels formed by the receptor complex itself. They are blocked by bicuculline and usually have modulatory sites sensitive to benzodiazepines and barbiturates. GABA-B receptors act through G-proteins on several effector systems, are insensitive to bicuculline, and have a high affinity for L-baclofen. GABA Receptors,Receptors, gamma-Aminobutyric Acid,gamma-Aminobutyric Acid Receptors,GABA Receptor,gamma-Aminobutyric Acid Receptor,Receptor, GABA,Receptor, gamma-Aminobutyric Acid,Receptors, gamma Aminobutyric Acid,gamma Aminobutyric Acid Receptor,gamma Aminobutyric Acid Receptors

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