Cation-chloride cotransporters in the nervous system

Maintenance of intracellular chloride (Cl⁻) concentration ([Cl⁻]i) is critical for volume regulation and determines the effects of γ-aminobutyric acid (GABA) and glycine-mediated neurotransmission. Cation-chloride cotransporters (CCC) transport Cl⁻ together with sodium (Na⁺), potassium (K⁺), or both, across plasma membranes and have an important role in maintenance [Cl⁻]i. The CCC in the nervous system include the Na–K–2Cl cotransporter NKCC1, which mediates Cl⁻ influx, and various K–Cl cotransporters, such as KCC2 and KCC3, that extrude Cl⁻ from the cell. NKCC1 mediates regulatory volume increase in response to cell shrinkage; KCC3 primarily mediates regulatory volume decrease in response to cell swelling. The precise balance between NKCC1 and KCC2 activity and their effect on [Cl⁻]i determines the consequences of GABAergic and glycinergic signaling in the nervous system. In immature neurons, the predominant effects of NKCC1 renders the effects of GABA and glycine depolarizing, which is important for development of neuronal circuits. In the adult nervous system, the predominant KCC2 action is critical for the inhibitory effects of GABA and glycine in most synaptic circuits. Increased activity of NKCC1 contributes to cerebral edema and excitotoxicity in the setting of traumatic or ischemic brain injury, whereas impaired activity of KCC2 renders GABAergic inhibition ineffective and contributes to the pathogenesis of seizures and pain. The molecular physiology of the CCC and their role in neurologic disorders have been the subjects of several comprehensive reviews.^1–11