Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore.
NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 119077, Singapore.
Cells. 2020 Jan 17;9(1):240. doi: 10.3390/cells9010240.
Dysfunctions in GABAergic inhibitory neural transmission occur in neuronal injuries and neurological disorders. The potassium-chloride cotransporter 2 (KCC2, SLC12A5) is a key modulator of inhibitory GABAergic inputs in healthy adult neurons, as its chloride (Cl) extruding activity underlies the hyperpolarizing reversal potential for GABA receptor Cl currents (E). Manipulation of KCC2 levels or activity improve symptoms associated with epilepsy and neuropathy. Recent works have now indicated that pharmacological enhancement of KCC2 function could reactivate dormant relay circuits in an injured mouse's spinal cord, leading to functional recovery and the attenuation of neuronal abnormality and disease phenotype associated with a mouse model of Rett syndrome (RTT). KCC2 interacts with Huntingtin and is downregulated in Huntington's disease (HD), which contributed to GABAergic excitation and memory deficits in the R6/2 mouse HD model. Here, these recent advances are highlighted, which attest to KCC2's growing potential as a therapeutic target for neuropathological conditions resulting from dysfunctional inhibitory input.
GABA 能抑制性神经传递功能障碍发生于神经元损伤和神经紊乱中。钾氯离子共转运蛋白 2（KCC2，SLC12A5）是健康成年神经元中 GABA 能抑制性传入的关键调节物，因为其氯离子（Cl）外排活性为 GABA 受体 Cl 电流（E）的超极化反转电位提供基础。KCC2 水平或活性的操纵可改善与癫痫和神经病变相关的症状。最近的研究表明，药理学增强 KCC2 功能可在受伤的小鼠脊髓中重新激活休眠的中继电路，从而导致功能恢复，并减轻与 Rett 综合征（RTT）小鼠模型相关的神经元异常和疾病表型。KCC2 与亨廷顿蛋白相互作用，并在亨廷顿病（HD）中下调，这导致 R6/2 小鼠 HD 模型中的 GABA 能兴奋和记忆缺陷。在此，强调了这些最新进展，证明 KCC2 作为治疗因抑制性输入功能障碍导致的神经病理学状况的治疗靶标具有越来越大的潜力。
