Steinberg S F, Brunton L L
Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Annu Rev Pharmacol Toxicol. 2001;41:751-73. doi: 10.1146/annurev.pharmtox.41.1.751.
There is a large body of functional data that supports the existence of subcellular compartmentation of the components of cyclic AMP action in the heart. Data from isolated perfused hearts and from purified ventricular myocytes imply a fixed and hormone-specific spatial relationship amongst components of cyclic AMP synthesis, response, and degradation. Available data demonstrate that within a cardiac myocyte, not all cyclic AMP gains access to all cyclic AMP-dependent protein kinase (PKA), that not all PKA interacts with all possible cellular substrates of PKA, and that only a subset of the myocyte's phosphodiesterases (PDEs) may degrade cyclic AMP after a given synthetic stimulus. Molecular mechanisms contributing to compartmentation are being discovered: localization of receptors, G proteins, and adenylyl cyclases in caveolar versus noncaveolar regions of the sarcolemma; localization of PKA by A-kinase anchoring proteins; localization of PKA substrates, PDE isoforms, and phosphoprotein phosphatases in discrete subcellular regions; and differential regulation of multiple isoforms of adenylyl cyclase, phosphoprotein phosphatase, and PDE in distinct subcellular compartments.
有大量功能数据支持心脏中cAMP作用成分存在亚细胞区室化。来自离体灌注心脏和纯化心室肌细胞的数据表明，cAMP合成、反应和降解成分之间存在固定且激素特异性的空间关系。现有数据表明，在心肌细胞内，并非所有cAMP都能接触到所有cAMP依赖性蛋白激酶（PKA），并非所有PKA都与PKA所有可能的细胞底物相互作用，并且在给定的合成刺激后，只有一部分心肌细胞磷酸二酯酶（PDE）可能降解cAMP。导致区室化的分子机制正在被发现：受体、G蛋白和腺苷酸环化酶在肌膜小窝与非小窝区域的定位；A激酶锚定蛋白对PKA的定位；PKA底物、PDE同工型和磷蛋白磷酸酶在离散亚细胞区域的定位；以及腺苷酸环化酶、磷蛋白磷酸酶和PDE多种同工型在不同亚细胞区室中的差异调节。
