Hyperpolarization-activated, cyclic nucleotide–gated (HCN) channels are important members of the voltage-gated pore loop channels family. They show unique features: they open at hyperpolarizing potential, carry a mixed Na/K current, and are regulated by cyclic nucleotides. Four different isoforms have been cloned (HCN1–4) that can assemble to form homo- or heterotetramers, characterized by different biophysical properties. These proteins are widely distributed throughout the body and involved in different physiologic processes, the most important being the generation of spontaneous electrical activity in the heart and the regulation of synaptic transmission in the brain. Their role in heart rate, neuronal pacemaking, dendritic integration, learning and memory, and visual and pain perceptions has been extensively studied; these channels have been found also in some peripheral tissues, where their functions still need to be fully elucidated. Genetic defects and altered expression of HCN channels are linked to several pathologies, which makes these proteins attractive targets for translational research; at the moment only one drug (ivabradine), which specifically blocks the hyperpolarization-activated current, is clinically available. This review discusses current knowledge about HCN channels, starting from their biophysical properties, origin, and developmental features, to (patho)physiologic role in different tissues and pharmacological modulation, ending with their present and future relevance as drug targets.

中文翻译：

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超极化激活的环核苷酸门控通道：从生物物理学到独特离子通道家族的药理学

超极化激活的环状核苷酸门控（HCN）通道是电压门控的孔环通道家族的重要成员。它们显示出独特的功能：它们在超极化电势下打开，携带混合的Na / K电流，并受环状核苷酸调控。已经克隆了四种不同的亚型（HCN1-4），它们可以组装形成同四聚体或异四聚体，其特征是具有不同的生物物理特性。这些蛋白质广泛分布于全身，并参与不同的生理过程，最重要的是心脏中自发的电活动的产生和大脑中突触传递的调节。已经广泛研究了它们在心率，神经元起搏，树突整合，学习和记忆以及视觉和疼痛知觉中的作用。在某些外周组织中也发现了这些通道，这些组织的功能仍需要充分阐明。遗传缺陷和HCN通道表达的改变与多种病理相关，这使这些蛋白质成为翻译研究的有吸引力的靶标。目前，临床上只有一种药物（伊伐布雷定）能特异性阻断超极化激活电流。这篇综述讨论了有关HCN通道的当前知识，从它们的生物物理特性，起源和发育特征开始，到在不同组织中的（病理）生理作用和药理学调控，最后以它们作为药物靶标的当前和未来的相关性结束。遗传缺陷和HCN通道表达的改变与多种病理相关，这使这些蛋白质成为翻译研究的有吸引力的靶标。目前，临床上只有一种药物（伊伐布雷定）能特异性阻断超极化激活电流。这篇综述讨论了有关HCN通道的当前知识，从它们的生物物理特性，起源和发育特征开始，到在不同组织中的（病理）生理作用和药理学调控，最后以它们作为药物靶标的当前和未来的相关性结束。遗传缺陷和HCN通道表达的改变与多种病理相关，这使这些蛋白质成为翻译研究的有吸引力的靶标。目前，临床上只有一种药物（伊伐布雷定）能特异性阻断超极化激活电流。这篇综述讨论了有关HCN通道的当前知识，从它们的生物物理特性，起源和发育特征，到在不同组织中的（病理）生理作用和药理学调控，最后以它们作为药物靶标的当前和未来相关性结束。