Neuronal K + -Cl - cotransporter KCC2 as a promising drug target for epilepsy treatment.

Autor: McMoneagle E; Institute of Biomedical and Clinical Sciences, Medical School, Faculty of Health and Life Sciences, University of Exeter, Hatherly Laboratories, Streatham Campus, Exeter, EX4 4PS, UK., Zhou J; Department of Neurology, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Biological Science, Zhongshan Hospital, Fudan University, Shanghai, 200032, China., Zhang S; Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital Xiamen University, School of Medicine, Xiamen University, Xiang'an Nan Lu, Xiamen, 361102, China., Huang W; State Key Laboratory of Chemical Biology, Research Center of Chemical Kinomics, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China., Josiah SS; Institute of Biomedical and Clinical Sciences, Medical School, Faculty of Health and Life Sciences, University of Exeter, Hatherly Laboratories, Streatham Campus, Exeter, EX4 4PS, UK., Ding K; State Key Laboratory of Chemical Biology, Research Center of Chemical Kinomics, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China. dingk@sioc.ac.cn., Wang Y; Department of Neurology, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Biological Science, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. yunwang@fudan.edu.cn., Zhang J; Institute of Biomedical and Clinical Sciences, Medical School, Faculty of Health and Life Sciences, University of Exeter, Hatherly Laboratories, Streatham Campus, Exeter, EX4 4PS, UK. jinweizhang@sioc.ac.cn.; Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital Xiamen University, School of Medicine, Xiamen University, Xiang'an Nan Lu, Xiamen, 361102, China. jinweizhang@sioc.ac.cn.; State Key Laboratory of Chemical Biology, Research Center of Chemical Kinomics, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China. jinweizhang@sioc.ac.cn.
Jazyk: angličtina
Zdroj: Acta pharmacologica Sinica [Acta Pharmacol Sin] 2024 Jan; Vol. 45 (1), pp. 1-22. Date of Electronic Publication: 2023 Sep 13.
DOI: 10.1038/s41401-023-01149-9
Abstrakt: Epilepsy is a prevalent neurological disorder characterized by unprovoked seizures. γ-Aminobutyric acid (GABA) serves as the primary fast inhibitory neurotransmitter in the brain, and GABA binding to the GABA A receptor (GABA A R) regulates Cl - and bicarbonate (HCO 3 - ) influx or efflux through the channel pore, leading to GABAergic inhibition or excitation, respectively. The neuron-specific K + -Cl - cotransporter 2 (KCC2) is essential for maintaining a low intracellular Cl - concentration, ensuring GABA A R-mediated inhibition. Impaired KCC2 function results in GABAergic excitation associated with epileptic activity. Loss-of-function mutations and altered expression of KCC2 lead to elevated [Cl - ] i and compromised synaptic inhibition, contributing to epilepsy pathogenesis in human patients. KCC2 antagonism studies demonstrate the necessity of limiting neuronal hyperexcitability within the brain, as reduced KCC2 functioning leads to seizure activity. Strategies focusing on direct (enhancing KCC2 activation) and indirect KCC2 modulation (altering KCC2 phosphorylation and transcription) have proven effective in attenuating seizure severity and exhibiting anti-convulsant properties. These findings highlight KCC2 as a promising therapeutic target for treating epilepsy. Recent advances in understanding KCC2 regulatory mechanisms, particularly via signaling pathways such as WNK, PKC, BDNF, and its receptor TrkB, have led to the discovery of novel small molecules that modulate KCC2. Inhibiting WNK kinase or utilizing newly discovered KCC2 agonists has demonstrated KCC2 activation and seizure attenuation in animal models. This review discusses the role of KCC2 in epilepsy and evaluates its potential as a drug target for epilepsy treatment by exploring various strategies to regulate KCC2 activity.
(© 2023. The Author(s).)
Databáze: MEDLINE
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