Jacobson K A, Hoffmann C, Cattabeni F, Abbracchio M P
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Apoptosis. 1999 Jun;4(3):197-211. doi: 10.1023/a:1009666707307.
Adenosine modulates the proliferation, survival and apoptosis of many different cell types, ranging from epithelial, endothelial and smooth muscle cells, to cells of the immune and neural lineages. In this review, we critically discuss the available in vitro and in vivo data which support a role for adenosine in both development-associated apoptosis, and in diseases characterized by either pathologically increased cell death (e.g., ischemia, trauma and aging-associated neurodegeneration) or abnormally reduced spontaneous apoptosis (e.g., cancer). Particular emphasis is given to the possible role of extracellular adenosine receptors, since these may represent novel and attractive molecular targets for the pharmacological modulation of apoptosis. In some instances, adenosine-induced cell death has been demonstrated to require entry of the nucleoside inside cells; however, in many other cases, activation of specific adenosine extracellular receptors has been demonstrated. Of the four G protein-coupled adenosine receptors so far identified, the A2A and the A3 receptors have been specifically implicated in modulation of cell death. For the A3 receptor, results obtained by exposing both cardiomyocytes and brain astrocytes to graded concentrations of selective agonists suggest induction of both cell protection and cell death. Such opposite effects, which likely depend on the degree of receptor activation, may have important therapeutic implications in the pharmacological modulation of cardiac and brain ischemia. For the A2A receptor, recent intriguing data suggest a specific role in immune cell death and immunosuppression, which may be relevant to both adenosine-deaminase-immunodeficiency syndrome (a pathology characterized by accumulation of adenosine to toxic levels) and in tumors where induction of apoptosis via activation of specific extracellular receptors may be desirable. Finally, preliminary data suggest that, in a similar way to the adenosine-deaminase-immunodeficiency syndrome, the abnormal accumulation of adenosine in degenerative muscular diseases may contribute to muscle cell death. Although the role of adenosine receptors in this effect still remains to be determined, these data suggest that adenosine-induced apoptosis may also represent a novel pathogenic pathway in muscular dystrophies.
腺苷可调节许多不同类型细胞的增殖、存活和凋亡，这些细胞类型包括上皮细胞、内皮细胞和平滑肌细胞，以及免疫和神经谱系的细胞。在本综述中，我们批判性地讨论了现有的体外和体内数据，这些数据支持腺苷在与发育相关的凋亡以及以病理性细胞死亡增加（如缺血、创伤和衰老相关的神经退行性变）或自发性凋亡异常减少（如癌症）为特征的疾病中所起的作用。我们特别强调细胞外腺苷受体的可能作用，因为它们可能代表了用于凋亡药理学调节的新型且有吸引力的分子靶点。在某些情况下，已证明腺苷诱导的细胞死亡需要核苷进入细胞内；然而，在许多其他情况下，已证明特定的细胞外腺苷受体被激活。在迄今已鉴定的四种G蛋白偶联腺苷受体中，A2A和A3受体已被明确牵涉到细胞死亡的调节中。对于A3受体，通过将心肌细胞和脑星形胶质细胞暴露于分级浓度的选择性激动剂所获得的结果表明，它既能诱导细胞保护又能诱导细胞死亡。这种可能取决于受体激活程度的相反作用，可能在心脏和脑缺血的药理学调节中具有重要的治疗意义。对于A2A受体，最近有趣的数据表明它在免疫细胞死亡和免疫抑制中具有特定作用，这可能与腺苷脱氨酶免疫缺陷综合征（一种以腺苷积累至毒性水平为特征的病理学）以及肿瘤相关，在肿瘤中通过激活特定的细胞外受体诱导凋亡可能是可取的。最后，初步数据表明，与腺苷脱氨酶免疫缺陷综合征类似，腺苷在退行性肌肉疾病中的异常积累可能导致肌肉细胞死亡。尽管腺苷受体在这种作用中的角色仍有待确定，但这些数据表明腺苷诱导的凋亡也可能代表肌营养不良症中的一种新的致病途径。
