Neuronal K^(+)-Cl^(-) cotransporter KCC2 as a promising drug target for epilepsy treatment  

作　　者：Erin McMoneagle Jin Zhou Shiyao Zhang Weixue Huang Sunday Solomon Josiah Ke Ding Yun Wang Jinwei Zhang 

机构地区：[1]Institute of Biomedical and Clinical Sciences,Medical School,Faculty of Health and Life Sciences,University of Exeter,Hatherly Laboratories,Streatham Campus,Exeter EX44PS,Uk [2]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 20o032,China [3]Institute of Cardiovascular Diseases,Xiamen Cardiovascular Hospital Xiamen University,School of Medicine,Xiamen University,Xiang'an Nan Lu,Xiamen 361102,China [4]State Key Laboratory of Chemical Biology,Research Center of Chemical Kinomics,Shanghai Instute of Organic Chemistry,Chinese Academy of Sciences,Shanghai 200032,China

出　　处：《Acta Pharmacologica Sinica》2024年第1期1-22,共22页中国药理学报（英文版）

基　　金：the financial support from the National Natural Science Foundation of China(Grant Nos.:82170406,81970238,and 32111530119);Shanghai Municipal Science and Technology Major Project(Grant No.:2018SHZDZX01);The Royal Society UK(Grant No.:IECINSFC/201094);The Commonwealth Scholarship Commission UK(Grant No.:NGCA-2020-43)。

摘　　要：Epilepsy is a prevalent neurological disorder characterized by unprovoked seizures.y-Aminobutyric acid(GABA)serves as the primary fast inhibitory neurotransmitter in the brain,and GABA binding to the GABAA receptor(GABAAR)regulates CI and bicarbonate(HCO3)influx or efflux through the channel pore,leading to GABAergic inhibition or excitation,respectively.The neuron-specific k+-cr cotransporter 2(KCC2)is essential for maintaining a low intracellular Cr concentration,ensuring GABAAR-mediated inhibition.Impaired KCC2 function results in GABAergic excitation associated with epileptic activity.Loss-offunction mutations and altered expression of KCC2 lead to elevated[CI];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.

关 键 词：EPILEPSY GABAergic inhibition K+-Cl-cotransporter KCC2 chloride homeostasis signaling regulatory pathways small molecularcompounds 

分 类 号：R742.1[医药卫生—神经病学与精神病学]