PDF(Pubmed)
Abstract：
In a family with inappropriate sinus tachycardia (IST), we identified a mutation (p.V240M) of the hyperpolarization-activated cyclic nucleotide-gated type 4 (HCN4) channel, which contributes to the pacemaker current (If) in human sinoatrial node cells. Here, we clinically study fifteen family members and functionally analyze the p.V240M variant. Macroscopic (IHCN4) and single-channel currents were recorded using patch-clamp in cells expressing human native (WT) and/or p.V240M HCN4 channels. All p.V240M mutation carriers exhibited IST that was accompanied by cardiomyopathy in adults. IHCN4 generated by p.V240M channels either alone or in combination with WT was significantly greater than that generated by WT channels alone. The variant, which lies in the N-terminal HCN domain, increased the single-channel conductance and opening frequency and probability of HCN4 channels. Conversely, it did not modify the channel sensitivity for cAMP and ivabradine or the level of expression at the membrane. Treatment with ivabradine based on functional data reversed the IST and the cardiomyopathy of the carriers. In computer simulations, the p.V240M gain-of-function variant increases If and beating rate and thus explains the IST of the carriers. The results demonstrate the importance of the unique HCN domain in HCN4, which stabilizes the channels in the closed state.
摘要：
在一个有不适当窦性心动过速(IST)的家庭中，我们确定了一个突变（p。V240M）的超极化激活的环核苷酸门控4型（HCN4）通道，这有助于人窦房结细胞中的起搏器电流（If）。这里,我们对15个家族成员进行了临床研究，并对p.V240M变异进行了功能分析。使用膜片钳在表达人天然(WT)和/或p.V240MHCN4通道的细胞中记录宏观(IHCN4)和单通道电流。所有p.V240M突变携带者在成人中表现出伴有心肌病的IST。由p.V240M通道单独或与WT组合产生的IHCN4显著大于由WT通道单独产生的IHCN4。变种,位于N端HCN结构域，增加了HCN4通道的单通道电导和开放频率和概率。相反，它没有改变cAMP和伊伐布雷定的通道敏感性或膜上的表达水平。基于功能数据的伊伐布雷定治疗逆转了IST和携带者的心肌病。在计算机模拟中，p.V240M功能增益变体增加了If和跳动率，从而解释了运营商的IST。结果证明HCN4中独特的HCN结构域的重要性,其在闭合状态下稳定通道。
