High resolution structural evidence suggests the Sarcoplasmic Reticulum forms microdomains with Acidic Stores (lysosomes) in the heart.
High resolution structural evidence suggests the Sarcoplasmic Reticulum forms microdomains with Acidic Stores (lysosomes) in the heart.
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DOI：
10.1038/srep40620
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发表时间：
2017-01-17
影响因子：
4.6
通讯作者：
Terrar DA
中科院分区：
文献类型：
--
作者：
Aston D;Capel RA;Ford KL;Christian HC;Mirams GR;Rog-Zielinska EA;Kohl P;Galione A;Burton RA;Terrar DA
烟酸腺嘌呤二核苷酸磷酸（NAADP）刺激钙从溶酶体等酸性储存中释放，是一种高效的钙动员第二信使。NAADP在基础条件下和β-肾上腺素应激后心脏钙信号传导中起重要作用。然而，酸性储存与心肌细胞中钙信号传导装置的其他部分的空间相互作用尚不清楚。我们提出的证据表明，溶酶体与心室肌细胞的肌浆网（SR）密切相关；二维电子显微镜和三维电子断层扫描的中位数间隔分别为20 nm和3.3 nm，表明这些细胞器之间存在真正的信号微域。免疫标记溶酶体的傅里叶分析显示为一种肌体模式（主导波长为1.80 μm）。此外，我们发现溶酶体与线粒体密切相关（3D研究中间隔6.2 nm），这可能为最近发现的NAADP在再灌注诱导的细胞死亡中的作用提供了基础。NAADP作用的触发假说提出，钙从酸性储存中释放随后会促进钙从SR中释放。这项工作提供了心肌细胞结构证据，表明酸性和SR钙储存之间形成微域，支持对心脏NAADP生理和药理学的新解释。
Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) stimulates calcium release from acidic stores such as lysosomes and is a highly potent calcium-mobilising second messenger. NAADP plays an important role in calcium signalling in the heart under basal conditions and following β-adrenergic stress. Nevertheless, the spatial interaction of acidic stores with other parts of the calcium signalling apparatus in cardiac myocytes is unknown. We present evidence that lysosomes are intimately associated with the sarcoplasmic reticulum (SR) in ventricular myocytes; a median separation of 20 nm in 2D electron microscopy and 3.3 nm in 3D electron tomography indicates a genuine signalling microdomain between these organelles. Fourier analysis of immunolabelled lysosomes suggests a sarcomeric pattern (dominant wavelength 1.80 μm). Furthermore, we show that lysosomes form close associations with mitochondria (median separation 6.2 nm in 3D studies) which may provide a basis for the recently-discovered role of NAADP in reperfusion-induced cell death. The trigger hypothesis for NAADP action proposes that calcium release from acidic stores subsequently acts to enhance calcium release from the SR. This work provides structural evidence in cardiac myocytes to indicate the formation of microdomains between acidic and SR calcium stores, supporting emerging interpretations of NAADP physiology and pharmacology in heart.