title: Current view on the functional regulation of the neuronal K(+)-Cl(-) cotransporter KCC2.
abstract: In the mammalian central nervous system (CNS), the inhibitory strength of chloride (Cl(-))-permeable GABAA and glycine receptors (GABAAR and GlyR) depends on the intracellular Cl(-) concentration ([Cl(-)]i). Lowering [Cl(-)]i enhances inhibition, whereas raising [Cl(-)]i facilitates neuronal activity. A neuron's basal level of [Cl(-)]i, as well as its Cl(-) extrusion capacity, is critically dependent on the activity of the electroneutral K(+)-Cl(-) cotransporter KCC2, a member of the SLC12 cation-Cl(-) cotransporter (CCC) family. KCC2 deficiency compromises neuronal migration, formation and the maturation of GABAergic and glutamatergic synaptic connections, and results in network hyperexcitability and seizure activity. Several neurological disorders including multiple epilepsy subtypes, neuropathic pain, and schizophrenia, as well as various insults such as trauma and ischemia, are associated with significant decreases in the Cl(-) extrusion capacity of KCC2 that result in increases of [Cl(-)]i and the subsequent hyperexcitability of neuronal networks. Accordingly, identifying the key upstream molecular mediators governing the functional regulation of KCC2, and modifying these signaling pathways with small molecules, might constitute a novel neurotherapeutic strategy for multiple diseases. Here, we discuss recent advances in the understanding of the mechanisms regulating KCC2 activity, and of the role these mechanisms play in neuronal Cl(-) homeostasis and GABAergic neurotransmission. As KCC2 mediates electroneutral transport, the experimental recording of its activity constitutes an important research challenge; we therefore also, provide an overview of the different methodological approaches utilized to monitor function of KCC2 in both physiological and pathological conditions.
authors.affiliation: INSERM, Institut de Neurobiologie de la Méditerranée (INMED) Marseille, France ; Aix-Marseille Université, UMR901 Marseille, France.
authors.forename: Igor
authors.initials: I
authors.lastname: Medina
authors.affiliation: INSERM, Institut de Neurobiologie de la Méditerranée (INMED) Marseille, France ; Aix-Marseille Université, UMR901 Marseille, France.
authors.forename: Perrine
authors.initials: P
authors.lastname: Friedel
authors.affiliation: INSERM, Institut de Neurobiologie de la Méditerranée (INMED) Marseille, France ; Aix-Marseille Université, UMR901 Marseille, France ; Neuroscience Center, University of Helsinki Helsinki, Finland.
authors.forename: Claudio
authors.initials: C
authors.lastname: Rivera
authors.affiliation: Department of Cardiology, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital Boston, MA, USA ; Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School Boston, MA, USA.
authors.forename: Kristopher T
authors.initials: KT
authors.lastname: Kahle
authors.affiliation: INSERM, Institut de Neurobiologie de la Méditerranée (INMED) Marseille, France ; Aix-Marseille Université, UMR901 Marseille, France.
authors.forename: Nazim
authors.initials: N
authors.lastname: Kourdougli
authors.affiliation: Institute of Biomedicine, Anatomy, University of Helsinki Helsinki, Finland.
authors.forename: Pavel
authors.initials: P
authors.lastname: Uvarov
authors.affiliation: INSERM, Institut de Neurobiologie de la Méditerranée (INMED) Marseille, France ; Aix-Marseille Université, UMR901 Marseille, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pellegrino
keywords: GABA; KCC2; intracellular chloride; neurons