Radwański Przemysław B, Johnson Christopher N, Györke Sándor, Veeraraghavan Rengasayee
Bob and Corinne Frick Center for Heart Failure and Arrhythmia, The Ohio State University Wexner Medical Center, Columbus, OH, United States.
Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States.
Front Physiol. 2018 Sep 4;9:1228. doi: 10.3389/fphys.2018.01228. eCollection 2018.
A nanodomain is a collection of proteins localized within a specialized, nanoscale structural environment, which can serve as the functional unit of macroscopic physiologic processes. We are beginning to recognize the key roles of cardiomyocyte nanodomains in essential processes of cardiac physiology such as electrical impulse propagation and excitation-contraction coupling (ECC). There is growing appreciation of nanodomain dysfunction, i.e., nanopathy, as a mechanistic driver of life-threatening arrhythmias in a variety of pathologies. Here, we offer an overview of current research on the role of nanodomains in cardiac physiology with particular emphasis on: (1) sodium channel-rich nanodomains within the intercalated disk that participate in cell-to-cell electrical coupling and (2) dyadic nanodomains located along transverse tubules that participate in ECC. The beat to beat function of cardiomyocytes involves three phases: the action potential, the calcium transient, and mechanical contraction/relaxation. In all these phases, cell-wide function results from the aggregation of the stochastic function of individual proteins. While it has long been known that proteins that exist in close proximity influence each other's function, it is increasingly appreciated that there exist nanoscale structures that act as functional units of cardiac biophysical phenomena. Termed nanodomains, these structures are collections of proteins, localized within specialized nanoscale structural environments. The nano-environments enable the generation of localized electrical and/or chemical gradients, thereby conferring unique functional properties to these units. Thus, the function of a nanodomain is determined by its protein constituents as well as their local structural environment, adding an additional layer of complexity to cardiac biology and biophysics. However, with the emergence of experimental techniques that allow direct investigation of structure and function at the nanoscale, our understanding of cardiac physiology and pathophysiology at these scales is rapidly advancing. Here, we will discuss the structure and functions of multiple cardiomyocyte nanodomains, and novel strategies that target them for the treatment of cardiac arrhythmias.
纳米域是位于特定纳米级结构环境中的蛋白质集合，可作为宏观生理过程的功能单元。我们开始认识到心肌细胞纳米域在心脏生理学的基本过程中所起的关键作用，如电冲动传播和兴奋-收缩偶联（ECC）。人们越来越认识到纳米域功能障碍，即纳米病，是多种病理状态下危及生命的心律失常的机制驱动因素。在此，我们概述了目前关于纳米域在心脏生理学中作用的研究，特别强调：（1）闰盘内富含钠通道的纳米域，其参与细胞间电偶联；（2）沿横管分布的二元纳米域，其参与ECC。心肌细胞的逐搏功能涉及三个阶段：动作电位、钙瞬变和机械收缩/舒张。在所有这些阶段，全细胞功能是由单个蛋白质的随机功能聚集而成。虽然早就知道紧密相邻的蛋白质会相互影响彼此的功能，但人们越来越认识到存在作为心脏生物物理现象功能单元的纳米级结构。这些结构被称为纳米域，是位于特定纳米级结构环境中的蛋白质集合。纳米环境能够产生局部的电和/或化学梯度，从而赋予这些单元独特的功能特性。因此，纳米域的功能由其蛋白质成分及其局部结构环境决定，这为心脏生物学和生物物理学增添了额外的复杂性。然而，随着能够直接研究纳米尺度结构和功能的实验技术的出现，我们对这些尺度下心脏生理学和病理生理学的理解正在迅速推进。在此，我们将讨论多个心肌细胞纳米域及其新颖的靶向治疗心律失常的策略。
