What physiological role does a slow hyperpolarization-activated ion channel with mixed cation selectivity play in the fast world of neuronal action potentials that are driven by depolarization? That puzzling question has piqued the curiosity of physiology enthusiasts about the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which are widely expressed across the body and especially in neurons. In this review, we emphasize the need to assess HCN channels from the perspective of how they respond to time-varying signals, while also accounting for their interactions with other co-expressing channels and receptors. First, we illustrate how the unique structural and functional characteristics of HCN channels allow them to mediate a slow negative feedback loop in the neurons that they express in. We present the several physiological implications of this negative feedback loop to neuronal response characteristics including neuronal gain, voltage sag and rebound, temporal summation, membrane potential resonance, inductive phase lead, spike triggered average, and coincidence detection. Next, we argue that the overall impact of HCN channels on neuronal physiology critically relies on their interactions with other co-expressing channels and receptors. Interactions with other channels allow HCN channels to mediate intrinsic oscillations, earning them the “pacemaker channel” moniker, and to regulate spike frequency adaptation, plateau potentials, neurotransmitter release from presynaptic terminals, and spike initiation at the axonal initial segment. We also explore the impact of spatially non-homogeneous subcellular distributions of HCN channels in different neuronal subtypes and their interactions with other channels and receptors. Finally, we discuss how plasticity in HCN channels is widely prevalent and can mediate different encoding, homeostatic, and neuroprotective functions in a neuron. In summary, we argue that HCN channels form an important class of channels that mediate a diversity of neuronal functions owing to their unique gating kinetics that made them a puzzle in the first place.

中文翻译：

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神秘的 HCN 通道：细胞神经生理学视角

具有混合阳离子选择性的慢速超极化激活离子通道在去极化驱动的神经元动作电位的快速世界中发挥什么生理作用？这个令人困惑的问题激起了生理学爱好者对超极化激活的环核苷酸门控（HCN）通道的好奇，该通道在全身，尤其是神经元中广泛表达。在这篇综述中，我们强调需要从 HCN 通道如何响应时变信号的角度来评估它们，同时还要考虑它们与其他共表达通道和受体的相互作用。首先，我们说明 HCN 通道独特的结构和功能特征如何使它们能够在它们表达的神经元中介导缓慢的负反馈回路。我们提出了这种负反馈回路对神经元反应特征的几种生理学影响，包括神经元增益、电压骤降​​和反弹、时间求和、膜电位共振、感应相位超前、尖峰触发平均值和重合检测。接下来，我们认为 HCN 通道对神经元生理学的总体影响关键取决于它们与其他共表达通道和受体的相互作用。与其他通道的相互作用使 HCN 通道能够介导内在振荡，从而获得“起搏器通道”的绰号，并调节尖峰频率适应、平台电位、突触前末梢的神经递质释放以及轴突起始段的尖峰起始。我们还探讨了不同神经元亚型中 HCN 通道的空间非均匀亚细胞分布的影响及其与其他通道和受体的相互作用。最后，我们讨论 HCN 通道的可塑性如何广泛存在，并如何介导神经元中的不同编码、稳态和神经保护功能。总之，我们认为 HCN 通道形成了一类重要的通道，由于其独特的门控动力学而介导多种神经元功能，这使得它们首先成为一个难题。