The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are voltage-gated ion channels that critically modulate neuronal activity. Four HCN subunits (HCN1-4) have been cloned, each having a unique expression profile and distinctive effects on neuronal excitability within the brain. Consistent with this, the expression and function of these subunits are altered in diverse ways in neurological disorders. Here, we review current knowledge on the structure and distribution of the individual HCN channel isoforms, their effects on neuronal activity under physiological conditions, and how their expression and function are altered in neurological disorders, particularly epilepsy, neuropathic pain, and affective disorders. We discuss the suitability of HCN channels as therapeutic targets and how drugs might be strategically designed to specifically act on particular isoforms. We conclude that medicines that target individual HCN isoforms and/or their auxiliary subunit, TRIP8b, may provide valuable means of treating distinct neurological conditions.

中文翻译：

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超极化激活的环核苷酸门控通道作为神经疾病的药物靶标。

超极化激活的环状核苷酸门控（HCN）通道是电压门控离子通道，可严格调节神经元活动。已克隆了四个HCN亚基（HCN1-4），每个亚基均具有独特的表达特征并对脑内神经元兴奋性具有独特的影响。与此相一致，这些亚基的表达和功能在神经系统疾病中以多种方式改变。在这里，我们回顾了当前有关单个HCN通道亚型的结构和分布，它们在生理条件下对神经元活动的影响以及它们在神经系统疾病（尤其是癫痫，神经性疼痛和情感性疾病）中的表达和功能如何变化的知识。我们讨论了HCN通道作为治疗靶点的适用性，以及如何策略性地设计药物以专门作用于特定同工型。我们得出的结论是，针对单个HCN亚型和/或其辅助亚基TRIP8b的药物可能会提供治疗不同神经系统疾病的宝贵手段。