Crossing the Chloride Channel: The Current and Potential Therapeutic Value of the Neuronal K-Cl Cotransporter KCC2.

Chloride (Cl) homeostasis is an essential process involved in neuronal signalling and cell survival. Inadequate regulation of intracellular Cl interferes with synaptic signalling and is implicated in several neurological diseases. The main inhibitory neurotransmitter of the central nervous system is -aminobutyric acid (GABA). GABA hyperpolarises the membrane potential by activating Cl permeable GABA receptor channels (GABAR). This process is reliant on Cl extruder K-Cl cotransporter 2 (KCC2), which generates the neuron's inward, hyperpolarising Cl gradient. KCC2 is encoded by the fifth member of the solute carrier 12 family ( and has remained a poorly understood component in the development and severity of many neurological diseases for many years. Recent advancements in next-generation sequencing and specific gene targeting, however, have indicated that loss of KCC2 activity is involved in a number of diseases including epilepsy and schizophrenia. It has also been implicated in neuropathic pain following spinal cord injury. Any variant of that negatively regulates the transporter's expression may, therefore, be implicated in neurological disease. A recent whole exome study has discovered several causative mutations in patients with epilepsy. Here, we discuss the implications of KCC2 in neurological disease and consider the evolving evidence for KCC2's potential as a therapeutic target.