University of California, Davis, Department of Pharmacology , 451 Health Sciences Drive, Genome and Biomedical Sciences Facility Room 3502, Davis, CA 95616 , USA +1 530 754 6135 ; +1 530 752 7710 ;
Expert Opin Ther Targets. 2013 Oct;17(10):1203-20. doi: 10.1517/14728222.2013.823161. Epub 2013 Jul 25.
KCa2 or small-conductance Ca(2+)-activated K(+) channels (SK) are expressed in many areas of the central nervous system where they participate in the regulation of neuronal afterhyperpolarization and excitability, and also serve as negative feedback regulators on the glutamate-NMDA pathway.
This review focuses on the role of KCa2 channels in learning and memory and their potential as therapeutic targets for Alzheimer's and Parkinson's disease, ataxia, schizophrenia and alcohol dependence.
There currently exists relatively solid evidence supporting the use of KCa2 activators for ataxia. Genetic KCa2 channel suppression in deep cerebellar neurons induces ataxia, while KCa2 activators like 1-EBIO, SKA-31 and NS13001 improve motor deficits in mouse models of episodic ataxia (EA) and spinal cerebellar ataxia (SCA). Use of KCa2 activators for ataxia is further supported by a report that riluzole improves ataxia in a small clinical trial. Based on accumulating literature evidence, KCa2 activators further appear attractive for the treatment of alcohol dependence and withdrawal. Regarding Alzheimer's disease, Parkinson's disease and schizophrenia, further research, including long-term studies in disease relevant animal models, will be needed to determine whether KCa2 channels constitute valid targets and whether activators or inhibitors would be needed to positively affect disease outcomes.
KCa2 或小电导钙激活钾（SK）通道在中枢神经系统的许多区域表达，它们参与神经元后超极化和兴奋性的调节，也作为谷氨酸-NMDA 途径的负反馈调节剂。
这篇综述重点介绍了 KCa2 通道在学习和记忆中的作用，以及它们作为阿尔茨海默病和帕金森病、共济失调、精神分裂症和酒精依赖的治疗靶点的潜力。
目前有相对确凿的证据支持使用 KCa2 激活剂治疗共济失调。在小脑深部神经元中抑制 KCa2 通道会导致共济失调，而 KCa2 激活剂，如 1-EBIO、SKA-31 和 NS13001，可改善发作性共济失调（EA）和脊髓小脑共济失调（SCA）小鼠模型中的运动缺陷。报道称，利鲁唑可在一项小型临床试验中改善共济失调，这进一步支持了使用 KCa2 激活剂治疗共济失调的观点。基于不断积累的文献证据，KCa2 激活剂进一步成为治疗酒精依赖和戒断的有吸引力的选择。关于阿尔茨海默病、帕金森病和精神分裂症，需要进一步的研究，包括在相关疾病动物模型中的长期研究，以确定 KCa2 通道是否构成有效靶点，以及是否需要激活剂或抑制剂来积极影响疾病结局。
