National Institute on Aging, NIH, Baltimore, MD 21224, USA.
Department of Cardiovascular Electrophysiology, The Johns Hopkins Hospital, Baltimore, MD 21287, USA.
Cells. 2024 Nov 14;13(22):1885. doi: 10.3390/cells13221885.
The rate of spontaneous action potentials (APs) generated by sinoatrial node cells (SANC) is regulated by local Ca release (LCR) from the sarcoplasmic reticulum via Ca release channels (ryanodine receptors, RyRs). LCR events propagate and self-organize within the network of RyR clusters (Ca release units, CRUs) via Ca-induced-Ca-release (CICR) that depends on CRU sizes and locations: While larger CRUs generate stronger release signals, the network's topology governs signal diffusion and propagation. This study used super-resolution structured illumination microscopy to image the 3D network of CRUs in rabbit SANC. The peripheral CRUs formed a spatial mesh, reflecting the cell surface geometry. Two distinct subpopulations of CRUs were identified within each cell, with size distributions conforming to a two-component Gamma mixture model. Furthermore, neighboring CRUs exhibited repulsive behavior. Functional properties of the CRU network were further examined in a novel numerical SANC model developed using our experimental data. Model simulations revealed that heterogeneities in both CRU sizes and locations CICR and increase the AP firing rate in a cooperative manner. However, these heterogeneities reduce the effect of β-adrenergic stimulation in terms of its in AP firing rate. The presence of heterogeneities in both sizes and locations allows SANC to reach higher during β-adrenergic stimulation. Thus, the CICR facilitation by heterogeneities in CRU sizes and locations regulates and optimizes cardiac pacemaker cell operation under various physiological conditions. Dysfunction of this optimization could be a key factor in heart rate reserve decline in aging and disease.
窦房结细胞（SANC）自发动作电位（AP）的产生速率受肌浆网通过钙释放通道（兰尼碱受体，RyR）释放的局部 Ca（LCR）调节。LCR 事件通过 Ca 诱导的 Ca 释放（CICR）在 RyR 簇（Ca 释放单位，CRU）网络中传播和自我组织，CICR 依赖于 CRU 大小和位置：虽然较大的 CRU 会产生更强的释放信号，但网络的拓扑结构决定了信号的扩散和传播。本研究使用超分辨率结构照明显微镜来成像兔 SANC 中 CRU 的 3D 网络。外围 CRU 形成了一个空间网格，反映了细胞表面的几何形状。在每个细胞内都鉴定出两种不同的 CRU 亚群，其大小分布符合双组份伽马混合模型。此外，相邻的 CRU 表现出排斥行为。使用我们的实验数据开发了一种新的数值 SANC 模型，进一步研究了 CRU 网络的功能特性。模型模拟表明，CRU 大小和位置的异质性以协同方式增加了 CICR，并增加了 AP 的发射速率。然而，这些异质性降低了β-肾上腺素能刺激对 AP 发射速率的影响。大小和位置的异质性的存在使得 SANC 在β-肾上腺素能刺激期间能够达到更高的频率。因此，CRU 大小和位置异质性的 CICR 促进作用调节和优化了各种生理条件下心脏起搏器细胞的运作。这种优化功能的失调可能是衰老和疾病中心率储备下降的关键因素。
