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Structural basis for modulation and agonist specificity of HCN pacemaker channels

机译：HCN起搏器通道的调制和激动剂特异性的结构基础

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摘要

The family of hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channels are crucial for a range of electrical signalling, including cardiac and neuronal pacemaker activity, setting resting membrane electrical properties and dendritic integration. These nonselective cation channels, underlying the I_f, I_h and I_q currents of heart and nerve cells, are activated by membrane hyperpolarization and modulated by the binding of cyclic nucleotides such as cAMP and cGMP. The cAMP-mediated enhancement of channel activity is largely responsible for the increase in heart rate caused by β-adrenergic agonists. Here we have investigated the mechanism underlying this modulation by studying a carboxy-terminal fragment of HCN2 containing the cyclic nucleotide-binding domain (CNBD) and the C-linker region that connects the CNBD to the pore. X-ray crystallographic structures of this C-terminal fragment bound to cAMP or cGMP, together with equilibrium sedimentation analysis, identify a tetramerization domain and the mechanism for cyclic nucleotide specificity, and suggest a model for ligand-dependent channel modulation. On the basis of amino acid sequence similarity to HCN channels, the cyclic nucleotide-gated, and eag- and KAT1-related families of channels are probably related to HCN channels in structure and mechanism.
机译：超极化激活，环状核苷酸调节（HCN）通道家族对于一系列电信号至关重要，包括心脏和神经元起搏器活动，设定静息膜电特性和树突状整合。这些非选择性阳离子通道位于心脏和神经细胞的I_f，I_h和I_q电流下，通过膜超极化激活，并通过环状核苷酸（如cAMP和cGMP）的结合进行调节。 cAMP介导的通道活性增强是β-肾上腺素能激动剂引起的心率增加的主要原因。在这里，我们通过研究HCN2的羧基末端片段（包含环状核苷酸结合结构域（CNBD）和将CNBD连接到孔的C接头区域），研究了这种调节的机制。与cAMP或cGMP结合的C末端片段的X射线晶体学结构，以及平衡沉降分析，确定了四聚结构域和环状核苷酸特异性机制，并提出了依赖配体的通道调节模型。根据与HCN通道的氨基酸序列相似性，环状核苷酸门控通道，eag和KAT1相关通道家族可能在结构和机制上与HCN通道有关。

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