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The Therapeutic Potential of Neuronal K-Cl Co-Transporter KCC2 in Huntington’s Disease and Its Comorbidities

Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Hatherly Laboratories, Exeter EX4 4PS, UK
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Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(23), 9142; https://doi.org/10.3390/ijms21239142
Received: 15 October 2020 / Revised: 16 November 2020 / Accepted: 28 November 2020 / Published: 30 November 2020
(This article belongs to the Special Issue Ion Channel and Ion-Related Signaling 2020)
Intracellular chloride levels in the brain are regulated primarily through the opposing effects of two cation-chloride co-transporters (CCCs), namely K+-Cl co-transporter-2 (KCC2) and Na+-K+-Cl co-transporter-1 (NKCC1). These CCCs are differentially expressed throughout the course of development, thereby determining the excitatory-to-inhibitory γ-aminobutyric acid (GABA) switch. GABAergic excitation (depolarisation) is important in controlling the healthy development of the nervous system; as the brain matures, GABAergic inhibition (hyperpolarisation) prevails. This developmental switch in excitability is important, as uncontrolled regulation of neuronal excitability can have implications for health. Huntington’s disease (HD) is an example of a genetic disorder whereby the expression levels of KCC2 are abnormal due to mutant protein interactions. Although HD is primarily considered a motor disease, many other clinical manifestations exist; these often present in advance of any movement abnormalities. Cognitive change, in addition to sleep disorders, is prevalent in the HD population; the effect of uncontrolled KCC2 function on cognition and sleep has also been explored. Several mechanisms by which KCC2 expression is reduced have been proposed recently, thereby suggesting extensive investigation of KCC2 as a possible therapeutic target for the development of pharmacological compounds that can effectively treat HD co-morbidities. Hence, this review summarizes the role of KCC2 in the healthy and HD brain, and highlights recent advances that attest to KCC2 as a strong research and therapeutic target candidate. View Full-Text
Keywords: GABAergic; Na+-K+-2Cl cotransporter 1 (NKCC1); K+-2Cl cotransporter 2 (KCC2); Chloride (Cl) homeostasis; Huntington’s disease; sleep disorders GABAergic; Na+-K+-2Cl cotransporter 1 (NKCC1); K+-2Cl cotransporter 2 (KCC2); Chloride (Cl) homeostasis; Huntington’s disease; sleep disorders
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MDPI and ACS Style

Andrews, K.; Josiah, S.S.; Zhang, J. The Therapeutic Potential of Neuronal K-Cl Co-Transporter KCC2 in Huntington’s Disease and Its Comorbidities. Int. J. Mol. Sci. 2020, 21, 9142. https://doi.org/10.3390/ijms21239142

AMA Style

Andrews K, Josiah SS, Zhang J. The Therapeutic Potential of Neuronal K-Cl Co-Transporter KCC2 in Huntington’s Disease and Its Comorbidities. International Journal of Molecular Sciences. 2020; 21(23):9142. https://doi.org/10.3390/ijms21239142

Chicago/Turabian Style

Andrews, Katie; Josiah, Sunday S.; Zhang, Jinwei. 2020. "The Therapeutic Potential of Neuronal K-Cl Co-Transporter KCC2 in Huntington’s Disease and Its Comorbidities" Int. J. Mol. Sci. 21, no. 23: 9142. https://doi.org/10.3390/ijms21239142

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