Potassium-chloride transporter member 5 (aka: KCC2 and SLC12A5) is a neuron-specific chloride potassium symporter responsible for establishing the chloride ion gradient in neurons through the maintenance of low intracellular chloride concentrations. It is a critical mediator of synaptic inhibition, cellular protection against excitotoxicity and may also act as a modulator of neuroplasticity. Potassium-chloride transporter member 5 is also known by the names: KCC2 (potassium chloride cotransporter 2) for its ionic substrates, and SLC12A5 for its genetic origin from the SLC12A5 gene in humans. Animals with reduced expression of this transporter exhibit severe motor deficits, epileptiform activity, and spasticity. KCC2 knockout animals, in which KCC2 is completely absent, die postnatally due to respiratory failure. Location KCC2 is a neuron-specific membrane protein expressed throughout the central nervous system, including the hippocampus, hypothalamus, brainstem, and motoneurons of the ventral spinal cord. At the subcellular level, KCC2 has been found in membranes of the somata and dendrites of neurons, with no evidence of expression on axons. KCC2 has also been shown to colocalize with GABAA receptors, which serve as ligand-gated ion channels to allow chloride ion movement across the cell membrane. Under normal conditions, the opening of GABAA receptors permits the hyperpolarizing influx of chloride ions to inhibit postsynaptic neurons from firing. Counterintuitively, KCC2 has also been shown to colocalize at excitatory synapses. One suggested explanation for such colocalization is a potential protective role of KCC2 against excitotoxicity. Ion influx due to the excitatory synaptic stimulation of ion channels in the neuronal membrane causes osmotic swelling of cells as water is drawn in alongside the ions. KCC2 may help to eliminate excess ions from the cell in order to re-establish osmotic homeostasis. Structure KCC2 is a member of the cation-chloride cotransporter (CCC) superfamily of proteins. As with all CCC proteins, KCC2 is an integral membrane protein with 12 transmembrane domains and both N- and C-terminal cytoplasmic domains. The terminal cytoplasmic domains can be phosphorylated by kinases within the neuron for rapid regulation. Two Isoforms: KCC2a, KCC2b There are two isoforms of KCC2: KCC2a and KCC2b. The two isoforms arise from alternative promoters on the SLC12A5 gene and differential splicing of the first mRNA exon. The isoforms differ in their N-termini, with the KCC2a form constituting the larger of the two splice variants. KCC2a levels remain relatively constant during pre- and postnatal development. KCC2b, on the other hand, is scarcely present during prenatal development and