Functional Microdomains in the Heart's Pacemaker: A New Dimension of Cardiac Remodeling

摘要 窦房结（SAN）功能障碍（SND）与窦房结中异常冲动形成和传播有关。 San.最近的估计表明，美国每年发生> 75，000例新的SND病例， 到2060年，这个数字将增加一倍以上。目前，外科植入永久性起搏器仍然是 然而，与药物治疗和成本相比，SND的最有效治疗是有限的 美国每年20亿美元。当代证据表明， SND中起搏蛋白的重塑（即与不同的空间受限微结构域相关）。我们 研究和其他研究表明，参与起搏活动的蛋白质与 特定的膜微区，小窝，即，小的（50 - 100 nm）质膜内陷 富含胆固醇、鞘脂和支架蛋白小窝蛋白-3（Cav3）。在这里，我们建议Cav3 组织专门的起搏信号复合体，提供肌膜之间的功能耦合， 蛋白质（称为表面“膜钟”）和亚细胞Ca2+机制（称为细胞外基质）。 "细胞内Ca2+时钟"）。我们假设，亚细胞靶向起搏蛋白的破坏， 相关的信号分子在结构重建的SAN，可能会影响他们的生物物理特性 和神经激素调节以及起搏信号复合物内的蛋白质-蛋白质相互作用 干扰动作电位的节律性产生，从而导致SND的病理生理学。这 研究引入了一个新的概念，即亚细胞内的变化引起的电生理变化。 结构重塑后信号传导复合物的区室化。它超越了传统的 电重构的概念，根据该概念，功能障碍可以通过直接增加来解释， 或单独降低蛋白质表达，并为心血管疾病增加了一个新的维度。本研究 将为复杂和更有效的治疗方法开辟全新的途径， 防止心脏细胞结构的退化。

ABSTRACT Sinoatrial node (SAN) dysfunction (SND) is associated with abnormal impulse formation and propagation in the SAN. Recent estimates suggest that >75,000 new cases of SND occur in the U.S. every year and that this number will more than double by 2060. At present, surgical implantation of permanent pacemakers remains the most efficient treatment of SND which, however, is limited when compared with pharmacologic therapy and costs $2 billion annually in the U.S. Contemporary evidence suggests an emerging role of compartmentalized remodeling (i.e. associated with distinct, spatially-confined micro-domains) of pacemaker proteins in SND. Our studies and others have demonstrated that the proteins involved in pacemaking activity are associated with specific membrane microdomains, caveolae, i.e., small (50–100 nm) invaginations of the plasma membrane enriched by cholesterol, sphingolipids and scaffolding proteins caveolin-3 (Cav3). Here, we propose that Cav3 organizes specialized pacemaker signaling complexes providing functional coupling between the sarcolemmal proteins (referred to as a surface ‘membrane clock’) and subcellular Ca2+ machinery (referred to as an ‘intracellular Ca2+ clock’). We hypothesize that disruption in subcellular targeting of pacemaker proteins and associated signaling molecules upon structural remodeling of the SAN, may affect their biophysical properties and neurohormonal regulation as well as protein-protein interactions within the pacemaker signaling complex disturbing rhythmic generation of action potentials and thus contributing to the pathophysiology of the SND. This research introduces a novel concept of electrophysiological changes resulting from alternations in the subcellular compartmentalization of signaling complexes following structural remodeling. This extends beyond the classical concept of electrical remodeling, according to which dysfunction can be explained by straightforward increases or decreases in protein expression alone, and adds a new dimension to cardiovascular disease. This research will open completely new avenues for sophisticated and more effective therapeutic approaches targeted at preventing the degradation of cardiac cytoarchitecture.