The role of HCN channels for the synchronization process in the sinoatrial node of the heart

HCN 通道在心脏窦房结同步过程中的作用

• 批准号: 274982784
• 负责人: Professor Dr. Martin Biel
• 金额: --
• 依托单位: Department Pharmazie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/274982784?language=en
• 关键词: role; HCN; channels; synchronization; process

Pacemaker channels are members of the hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels and are considered essential motors for the generation of the heart beat in the sinoatrial node (SAN) of the heart. Four channel subtypes, HCN1-HCN4 are found in humans and mice. HCN4 represents the major isoform and is expressed throughout the SAN. HCN channels are opened by hyperpolarization. In addition, activation of the channels is regulated by cyclic adenosine monophosphate (cAMP). In this context, an increase in intracellular cAMP concentration, as it occurs during sympathetic nervous system activation, leads to an increase in HCN channel activity. In the previous proposal, we addressed the question how the secondary messenger cAMP regulates heartbeat via an effect on HCN4 channels. To address this question, we generated knock-in mice in which cAMP can no longer bind to HCN4. By studying single pacemaker cells from the SAN, we observed that SAN cells can not only adopt the well-known mode in which the cells fire spontaneous action potentials and drive the heartbeat (firing mode), but can also adopt a non-firing mode in which the cells remain quiescent for a period of up to 1 minute. We have evidence that pacemaker cells in non-firing mode act as "brakes" in the SAN network, inhibiting the activity of neighboring pacemaker cells in firing mode. Our hypothesis is that in the network of the SAN, the number of cells in non-firing mode is adjusted by the cAMP-dependent regulation of HCN4. Accordingly, the precise dose for inhibition within the sinus node could be adjusted according to the situation via the cAMP-dependent regulation of HCN4. Thus, heart rate could be effectively stabilized. Furthermore, we hypothesize that cAMP-dependent regulation of HCN1 and HCN2 may be of similar importance as cAMP-dependent regulation of HCN4. These hypotheses will be investigated in vitro and in vivo in this follow-up proposal. Taken together, we expect the findings obtained in this proposal to provide important information about the pacing mechanism as well as to understand how dysfunction of HCN channels leads to the sick sinus syndrome.

起搏器通道是超极化激活的环核苷酸门控（HCN）阳离子通道的成员，并且被认为是在心脏的窦房结（SAN）中产生心脏搏动的必需马达。在人类和小鼠中发现了四种通道亚型HCN 1-HCN 4。HCN 4代表主要同种型，并在整个SAN中表达。HCN通道通过超极化打开。此外，通道的激活受环磷酸腺苷（cAMP）调节。在这种情况下，细胞内cAMP浓度的增加，因为它发生在交感神经系统激活，导致HCN通道活性的增加。在先前的提案中，我们解决了第二信使cAMP如何通过对HCN 4通道的影响来调节心跳的问题。为了解决这个问题，我们产生了敲入小鼠，其中cAMP不再与HCN 4结合。通过研究来自SAN的单个起搏细胞，我们观察到SAN细胞不仅可以采用众所周知的模式，其中细胞激发自发动作电位并驱动心跳（激发模式），而且还可以采用非激发模式，其中细胞保持静止长达1分钟。我们有证据表明，处于非放电模式的起搏细胞在SAN网络中充当“刹车”，抑制处于放电模式的相邻起搏细胞的活动。我们的假设是，在SAN的网络中，非放电模式的细胞数量是由cAMP依赖性的HCN 4调节的。因此，窦房结内抑制的精确剂量可以根据情况通过cAMP依赖性调节HCN 4进行调整。因此，可以有效地稳定心率。此外，我们假设cAMP依赖性调节HCN 1和HCN 2可能与cAMP依赖性调节HCN 4具有相似的重要性。这些假设将在体外和体内进行研究，在这个后续的建议。综上所述，我们期望本研究的结果能够提供有关起搏机制的重要信息，并了解HCN通道功能障碍如何导致病窦综合征。