Myocardial Function, National Heart and Lung Institute, Imperial College London, ICTEM, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Cell Rep. 2018 Apr 10;23(2):459-469. doi: 10.1016/j.celrep.2018.03.053.
Cardiomyocytes from the apex but not the base of the heart increase their contractility in response to β-adrenoceptor (βAR) stimulation, which may underlie the development of Takotsubo cardiomyopathy. However, both cell types produce comparable cytosolic amounts of the second messenger cAMP. We investigated this discrepancy using nanoscale imaging techniques and found that, structurally, basal cardiomyocytes have more organized membranes (higher T-tubular and caveolar densities). Local membrane microdomain responses measured in isolated basal cardiomyocytes or in whole hearts revealed significantly smaller and more short-lived βAR/cAMP signals. Inhibition of PDE4, caveolar disruption by removing cholesterol or genetic deletion of Cav3 eliminated differences in local cAMP production and equilibrated the contractile response to βAR. We conclude that basal cells possess tighter control of cAMP because of a higher degree of signaling microdomain organization. This provides varying levels of nanostructural control for cAMP-mediated functional effects that orchestrate macroscopic, regional physiological differences within the heart.
心尖部位的心肌细胞而非心脏底部的心肌细胞会在β-肾上腺素能受体（βAR）刺激下增加收缩力，这可能是 Takotsubo 心肌病发展的基础。然而，这两种细胞类型都能产生相当数量的细胞内信使 cAMP。我们使用纳米级成像技术研究了这一差异，发现从结构上看，基底心肌细胞的膜结构更有序（T 管和 caveolae 的密度更高）。在分离的基底心肌细胞或整个心脏中测量的局部膜微区反应显示，βAR/cAMP 信号更小、更短暂。抑制 PDE4、去除胆固醇破坏 caveolae 或 Cav3 基因缺失消除了局部 cAMP 产生的差异，并使βAR 引起的收缩反应平衡。我们得出结论，基底细胞对 cAMP 的控制更严格，因为信号微区组织程度更高。这为 cAMP 介导的功能效应提供了不同程度的纳米结构控制，从而协调心脏内宏观区域的生理差异。
