Department of Biosciences, University of Milan, Milan, Italy.
Department of Biology, Technical University Darmstadt, Darmstadt, Germany.
Biochem Soc Trans. 2021 Dec 17;49(6):2573-2579. doi: 10.1042/BST20210290.
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are primarily activated by voltage and further modulated by cAMP. While cAMP binding alone does not open the channel, its presence facilitates the action of voltage, increasing channel open probability. Functional results indicate that the membrane-based voltage sensor domain (VSD) communicates with the cytosolic cyclic nucleotide-binding domain (CNBD), and vice-versa. Yet, a mechanistic explanation on how this could occur in structural terms is still lacking. In this review, we will discuss the recent advancement in understanding the molecular mechanisms connecting the VSD with the CNBD in the tetrameric organization of HCN channels unveiled by the 3D structures of HCN1 and HCN4. Data show that the HCN domain transmits cAMP signal to the VSD by bridging the cytosolic to the membrane domains. Furthermore, a metal ion coordination site connects the C-linker to the S4-S5 linker in HCN4, further facilitating cAMP signal transmission to the VSD in this isoform.
超极化激活环核苷酸门控 (HCN) 通道主要由电压激活，并进一步受 cAMP 调节。虽然 cAMP 结合本身不能打开通道，但它的存在促进了电压的作用，增加了通道的开放概率。功能结果表明，基于膜的电压传感器域 (VSD) 与胞质环核苷酸结合域 (CNBD) 相互通讯，反之亦然。然而，关于这种结构如何发生的机械解释仍然缺乏。在这篇综述中，我们将讨论最近在理解连接 VSD 与 CNBD 的分子机制方面的进展，这些机制是由 HCN1 和 HCN4 的三维结构揭示的 HCN 通道的四聚体组织。数据表明，HCN 结构域通过桥接胞质和膜结构域将 cAMP 信号传递到 VSD。此外，在 HCN4 中，一个金属离子配位位点将 C 连接子与 S4-S5 连接子连接起来，进一步促进了这种异构体中 cAMP 信号向 VSD 的传递。
