Biological Physics Group, Department of Physics and Astronomy, The University of Manchester, Manchester M13 9PL, UK.
Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
Int J Mol Sci. 2021 Apr 30;22(9):4761. doi: 10.3390/ijms22094761.
Robust, spontaneous pacemaker activity originating in the sinoatrial node (SAN) of the heart is essential for cardiovascular function. Anatomical, electrophysiological, and molecular methods as well as mathematical modeling approaches have quite thoroughly characterized the transmembrane fluxes of Na, K and Ca that produce SAN action potentials (AP) and 'pacemaker depolarizations' in a number of different in vitro adult mammalian heart preparations. Possible ionic mechanisms that are responsible for SAN primary pacemaker activity are described in terms of: (i) a Ca-regulated mechanism based on a requirement for phasic release of Ca from intracellular stores and activation of an inward current-mediated by Na/Ca exchange; (ii) time- and voltage-dependent activation of Na or Ca currents, as well as a cyclic nucleotide-activated current, I; and/or (iii) a combination of (i) and (ii). Electrophysiological studies of single spontaneously active SAN myocytes in both adult mouse and rabbit hearts consistently reveal significant expression of a rapidly activating time- and voltage-dependent K current, often denoted I, that is selectively expressed in the leading or primary pacemaker region of the adult mouse SAN. The main goal of the present study was to examine by combined experimental and simulation approaches the functional or physiological roles of this K current in the pacemaker activity. Our patch clamp data of mouse SAN myocytes on the effects of a pharmacological blocker, E4031, revealed that a rapidly activating K current is essential for action potential (AP) repolarization, and its deactivation during the pacemaker potential contributes a small but significant component to the pacemaker depolarization. Mathematical simulations using a murine SAN AP model confirm that well known biophysical properties of a delayed rectifier K current can contribute to its role in generating spontaneous myogenic activity.
心脏的窦房结（SAN）中产生的稳健、自发的起搏器活动对于心血管功能至关重要。解剖学、电生理学和分子方法以及数学建模方法已经相当彻底地描述了产生 SAN 动作电位（AP）和“起搏器去极化”的跨膜 Na、K 和 Ca 通量，这些方法在许多不同的体外成年哺乳动物心脏制剂中都得到了应用。描述了可能负责 SAN 原发性起搏器活动的离子机制，包括：（i）基于细胞内储存的 Ca 相释放和 Na/Ca 交换激活内向电流的 Ca 调节机制；（ii）Na 或 Ca 电流以及环核苷酸激活电流 I 的时变和电压依赖性激活；和/或（iii）（i）和（ii）的组合。在成年小鼠和兔心脏的单个自发活动的 SAN 心肌细胞的电生理学研究中，一致发现显著表达快速激活的时变和电压依赖性 K 电流，通常表示为 I，该电流仅在成年小鼠 SAN 的主导或原发性起搏器区域表达。本研究的主要目的是通过结合实验和模拟方法来研究这种 K 电流在起搏器活动中的功能或生理作用。我们对小鼠 SAN 心肌细胞的膜片钳数据表明，一种快速激活的 K 电流对于动作电位（AP）复极化至关重要，并且其在起搏器电位期间的失活对起搏器去极化贡献了一个小但重要的组成部分。使用鼠类 SAN AP 模型的数学模拟证实了延迟整流器 K 电流的众所周知的生物物理特性可以有助于其在产生自发肌源性活动中的作用。
