Sebastian Sonia, Nobles Muriel, Tsisanova Elena, Ludwig Andreas, Munroe Patricia B, Tinker Andrew
Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universität Erlangen-Nürnberg, Erlangen, Germany.
Physiol Genomics. 2021 Apr 1;53(4):150-159. doi: 10.1152/physiolgenomics.00157.2020. Epub 2021 Mar 15.
We have assessed the role of ric-b8 in the control of heart rate after the gene was implicated in a recent genome-wide association study of resting heart rate. We developed a novel murine model in which it was possible to conditionally delete ric-8b in the sinoatrial (SA) node after the addition of tamoxifen. Despite this, we were unable to obtain homozygotes and thus studied heterozygotes. Haploinsufficiency of ric-8b in the sinoatrial node induced by the addition of tamoxifen in adult animals leads to mice with a reduced heart rate. However, other electrocardiographic intervals (e.g., PR and QRS) were normal, and there was no apparent arrhythmia such as heart block. The positive chronotropic response to isoprenaline was abrogated, whereas the response to carbachol was unchanged. The pacemaker current I (funny current) has an important role in regulating heart rate, and its function is modulated by both isoprenaline and carbachol. Using a heterologous system expressing HCN4, we show that ric-8b can modulate the HCN4 current. Overexpression of ric-8b led to larger HCN4 currents, whereas silencing ric-8b led to smaller currents. Ric-8b modulates heart rate responses in vivo likely via its actions on the stimulatory G-protein.
在最近一项关于静息心率的全基因组关联研究中发现ric - 8b基因与心率控制有关后，我们评估了ric - 8b在心率控制中的作用。我们构建了一种新型小鼠模型，在该模型中，添加他莫昔芬后可在窦房结中条件性删除ric - 8b。尽管如此，我们无法获得纯合子，因此研究了杂合子。成年动物中添加他莫昔芬诱导窦房结中ric - 8b单倍剂量不足会导致小鼠心率降低。然而，其他心电图间期（如PR和QRS）正常，且没有明显的心律失常，如心脏传导阻滞。对异丙肾上腺素的正性变时反应被消除，而对卡巴胆碱的反应未改变。起搏电流I（起搏电流）在调节心率中起重要作用，其功能受异丙肾上腺素和卡巴胆碱的调节。使用表达HCN4的异源系统，我们发现ric - 8b可以调节HCN4电流。ric - 8b的过表达导致更大的HCN4电流，而ric - 8b的沉默导致更小的电流。Ric - 8b可能通过其对刺激性G蛋白的作用在体内调节心率反应。
