HCN channels sense temperature and determine heart rate responses to heat.
HCN channels sense temperature and determine heart rate responses to heat.
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HCN 通道感知温度并确定心率对热的反应。
DOI：
10.1101/2023.09.02.556046
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Anderson,MarkE
中科院分区：
文献类型：
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作者：
Wu,Yuejin;Wang,Qinchuan;Granger,Jonathan;Gaido,OscarReyes;Aguilar,EricNunez;Ludwig,Andreas;Moroni,Anna;Bianchet,MarioA;Anderson,MarkE
超极化激活的环核苷酸门控离子通道4 （HCN4）电流由于cAMP的结合而增加，并且被公认有助于肾上腺素能驱动的心率加速。HCN4电流也以一种未知的机制随热量增加。我们使用热力学和同源性计算模型、位点定向诱变和小鼠模型来确定HCN4通道（M407/Y409）的S4-S5连接体上的一个简洁的基序，该基序决定HCN4电流（If）对热的响应。该基序是心脏起搏器细胞、离体心脏和体内热触发速率加速所必需的。令人惊讶的是，M407/Y409基序列突变的功能缺失不仅阻止了正常的热反应，还阻止了cAMP的反应，这表明S4-S5连接体中的热感测机制对于cAMP变构途径的操作是必不可少的，并且是HCN4门控调制的核心。M407/Y409基序列在所有HCN家族成员中都是保守的，这表明HCN通道广泛参与了热耦合到细胞膜兴奋性变化的过程。
Thehyperpolarization-activatedcyclicnucleotide-gated ion channel 4 (HCN4) current increases due to cAMP binding and is well-recognized to contribute to adrenergically driven heart rate acceleration. HCN4 current also increases with heat by an unknown mechanism(s). We use thermodynamical and homology computational modeling, site-directed mutagenesis, and mouse models to identify a concise motif on the S4-S5 linker of HCN4 channels (M407/Y409) that determines HCN4 current (If) responses to heat. This motif is required for heat-triggered rate acceleration in cardiac pacemaker cells, isolated hearts and in vivo. Surprisingly, a loss of function M407/Y409 motif mutation prevented not only normal heat but also cAMP responses, suggesting that the heat-sensing machinery within the S4-S5 linker is essential for operating the cAMP allosteric pathway and is central to HCN4 gating modulation. The M407/Y409 motif is conserved across all HCN family members suggesting that HCN channels participate broadly in coupling heat to changes in cell membrane excitability.