Potassium-chloride transporter member 5 (KCC2/SLC12A5) is a neuron-specific chloride potassium symporter related to establishing the chloride ion gradient in neurons through the maintenance of low intracellular chloride concentrations. It is a vital mediator of synaptic inhibition and cellular protection against excitotoxicity. It may also act as a modulator of neuroplasticity. SLC12A5 can function as ionic substrates. It has been reported that animals with the reduced expression of SLC12A5 exhibit severe motor deficits, epileptiform activity, and spasticity. SLC12A5 knockout animals will die postnatally due to respiratory failure.
|Basic Information of SLC12A5|
|Protein Name||Solute carrier family 12 member 5|
|Aliases||Electroneutral potassium-chloride cotransporter 2, K-Cl cotransporter 2, Neuronal K-Cl cotransporter|
|Organism||Homo sapiens (Human)|
KCC2 or SLC12A5 is a potassium (K+)/chloride (Cl-) symporter that controls chloride homeostasis in neurons. It is responsible for classical postsynaptic with the help of GABAA receptors and glycine receptors in the central nervous system. KCC2 uses the potassium gradient generated by the Na+/K+ pump to drive chloride extrusion from neurons. Cellular swelling can be brought by KCC2 as osmotically-obliged water is drawn into neurons along with ionic solutes. KCC2 has been reported to be stimulated by cell-swelling and therefore affect eliminating excess ions following periods of high stimulation in order to maintain steady-state neuronal volume and prevent cells from bursting. Moreover, KCC2 plays a critical role in the glutamatergic synapses within the central nervous system. Neurons without KCC2 have stunted dendritic growth and malformed dendritic spines, thus suggesting KCC2 plays a critical role in the structure and function of dendritic spines which host most excitatory synapses in cortical neurons. By interacting 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.
Fig.1 GABAA signaling shifts from depolarizing to hyperpolarizing responses during development. (Moore, 2017)
This article shows that KCC2 knockout mice die immediately after birth due to severe motor deficits. It also reveals abnormal spontaneous electrical activity and alters spinal cord responses to peripheral electrical stimuli.
The article demonstrates a novel mechanism under which BDNF/TrkB signaling restrains chloride-dependent fast GABAergic inhibition. This process can contribute to the well-known role of TrkB-activated signaling cascades in the induction and establishment of epileptic activity.
The authors find that the plasmalemmal KCC2 has a very high rate of turnover. It is companied with a time frame that suggests a novel role for changes in KCC2 expression in diverse manifestations. It means that downregulation of KCC2 may be a general early response to various kinds of neuronal trauma.
These results open new perspectives for the development of therapeutic strategies for alleviating spasticity.
The article tells us that the down-regulation of KCC2 under pathophysiological conditions (epilepsy, damage) in mature neuron seems to reflect a 'recapitulation' of early developmental mechanisms and this may be a prerequisite for the re-establishment of connectivity in damaged brain tissue.
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