Department of Pharmacology, University of California, San Diego, La Jolla, 92093-0636, USA.
Acta Physiol (Oxf). 2012 Feb;204(2):277-87. doi: 10.1111/j.1748-1716.2011.02273.x. Epub 2011 May 26.
The second messenger cyclic AMP (cAMP) can either stimulate or inhibit programmed cell death (apoptosis). Here, we review examples of cell types that show pro-apoptotic or anti-apoptotic responses to increases in cAMP. We also show that cells can have both such responses, although predominantly having one or the other. Protein kinase A (PKA)-promoted changes in phosphorylation and gene expression can mediate pro-apoptotic responses, such as in murine S49 lymphoma cells, based on evidence that mutants lacking PKA fail to undergo cAMP-promoted, mitochondria-dependent apoptosis. Mechanisms for the anti-apoptotic response to cAMP likely involve Epac (Exchange protein activated by cAMP), a cAMP-regulated effector that is a guanine nucleotide exchange factor (GEF) for the low molecular weight G-protein, Rap1. Therapeutic approaches that activate PKA-mediated pro-apoptosis or block Epac-mediated anti-apoptotisis may provide a means to enhance cell killing, such as in certain cancers. In contrast, efforts to block PKA or stimulate Epac have the potential to be useful in diseases settings (such as heart failure) associated with cAMP-promoted apoptosis.
第二信使环腺苷酸 (cAMP) 既可以刺激也可以抑制程序性细胞死亡（细胞凋亡）。在这里，我们回顾了一些细胞类型的例子，这些细胞类型对 cAMP 的增加表现出促凋亡或抗凋亡的反应。我们还表明，细胞可以同时具有这两种反应，尽管主要表现为一种或另一种。蛋白激酶 A (PKA) 促进的磷酸化和基因表达变化可以介导促凋亡反应，例如在鼠 S49 淋巴瘤细胞中，这基于缺乏 PKA 的突变体不能经历 cAMP 促进的、线粒体依赖性细胞凋亡的证据。对 cAMP 的抗凋亡反应的机制可能涉及 Epac（cAMP 激活的交换蛋白），Epac 是一种 cAMP 调节的效应物，是低分子量 G 蛋白 Rap1 的鸟嘌呤核苷酸交换因子 (GEF)。激活 PKA 介导的促凋亡或阻断 Epac 介导的抗凋亡的治疗方法可能提供增强细胞杀伤的手段，例如在某些癌症中。相比之下，阻止 PKA 或刺激 Epac 的努力有可能在与 cAMP 促进的细胞凋亡相关的疾病环境（如心力衰竭）中有用。
