[8][9][10][11] 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.
[8] 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.
Under normal conditions, the opening of GABAA receptors permits the hyperpolarizing influx of chloride ions to inhibit postsynaptic neurons from firing.
[8] KCC2b knockout mice can survive up to postnatal day 17 (P17) due to the presence of functional KCC2a alone, but they exhibit low body weight, motor deficits and generalized seizures.
[16] Oligomerization may play an important role in transporter function and activation, as it has been observed that the oligomer to monomer ratio increases in correlation to the development of the chloride ion gradient in neurons.
Loss of KCC2 following neuronal damage (i.e. ischemia, spinal cord damage, physical trauma to the central nervous system) results in the loss of inhibitory regulation and the subsequent development of neuronal hyperexcitability, motor spasticity, and seizure-like activity[10] as GABAA receptors and glycine receptors revert from hyperpolarizing to depolarizing postsynaptic effects.
[6] KCC2 has been shown to be activated by cell-swelling, and may therefore play a role in eliminating excess ions following periods of high stimulation in order to maintain steady-state neuronal volume and prevent cells from bursting.
[8] Recent studies demonstrate that KCC2 plays a critical role in the structure and function of dendritic spines[9] which host most excitatory synapses in cortical neurons.
Through an interaction with actin cytoskeleton, KCC2 forms a molecular barrier to the diffusion of transmembrane proteins within dendritic spines, thereby regulating the local confinement of AMPA receptors and synaptic potency.
[18] KCC2 is transcriptionally downregulated following central nervous system injury by the TrkB receptor signalling transduction cascade (activated by BDNF and NT-4/5).
[11][22] This process involves rapid dephosphorylation on Ser940 and calpain protease cleavage of KCC2, leading to enhanced membrane diffusion and endocytosis of the transporter,[23] as demonstrated in experiments using single particle tracking.