Abstract
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 γ-aminobutyric acid (GABA). GABA hyperpolarises the membrane potential by activating Cl− permeable GABAA receptor channels (GABAAR). 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 (SLC12A5) 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 SLC12A5 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.
Highlights
Chloride (Cl−) is an abundant anion involved in a variety of physiological processes including gene regulation [1, 2], pH maintenance [3], and control of cell volume [4]
These findings indicate that even partial disruption to neuronal Cl− extrusion, mediated by two impaired variants of solute carrier family (SLC A), causes epilepsy of infancy with migrating focal seizures (EIMFS)
KCC2 is a key player in the maintenance of neuronal Cl− homeostasis
Summary
Chloride (Cl−) is an abundant anion involved in a variety of physiological processes including gene regulation [1, 2], pH maintenance [3], and control of cell volume [4]. In healthy adult neuron’s [Cl−]i is usually maintained at a low concentration, enabling inhibitory, hyperpolarising GABAergic signalling [15] This constitutes the main role of GABA in CNS neurotransmission; its potential dysfunction in neurological disease due to dysregulated cellular Cl− levels is, of significant interest. In Huntington’s disease positive rat models, upregulation of NKCC1 and loss of KCC2 caused GABA mediated stimulation to switch from an inhibitory to excitatory response [28] These studies suggest that researching expression patterns of KCC2 may further our understanding of the aetiology of these diseases. HEK293 are an embryonic kidney cell line commonly used in the analysis of ion homeostasis Both KCC2 isoforms are predominantly expressed in neurons of the brain and spinal cord, organs with several physiological and functional differences to the kidney. Upregulation of the cotransporter may indicate onset or previous infliction of neurological insult
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