Department of Metabolism and Cell Signalling, Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Madrid 28029, Spain.
Biol Rev Camb Philos Soc. 2013 Aug;88(3):645-68. doi: 10.1111/brv.12020. Epub 2013 Jan 29.
Cyclic AMP (cAMP) plays a key regulatory role in most types of cells; however, the pathways controlled by cAMP may present important differences between organisms and between tissues within a specific organism. Changes in cAMP levels are caused by multiple triggers, most affecting adenylyl cyclases, the enzymes that synthesize cAMP. Adenylyl cyclases form a large and diverse family including soluble forms and others with one or more transmembrane domains. Regulatory mechanisms for the soluble adenylyl cyclases involve either interaction with diverse proteins, as happens in Escherichia coli or yeasts, or with calcium or bicarbonate ions, as occurs in mammalian cells. The transmembrane cyclases can be regulated by a variety of proteins, among which the α subunit and the βγ complex from G proteins coupled to membrane receptors are prominent. cAMP levels also are controlled by the activity of phosphodiesterases, enzymes that hydrolyze cAMP. Phosphodiesterases can be regulated by cAMP, cGMP or calcium-calmodulin or by phosphorylation by different protein kinases. Regulation through cAMP depends on its binding to diverse proteins, its proximal targets, this in turn causing changes in a variety of distal targets. Specifically, binding of cAMP to regulatory subunits of cAMP-dependent protein kinases (PKAs) affects the activity of substrates of PKA, binding to exchange proteins directly activated by cAMP (Epac) regulates small GTPases, binding to transcription factors such as the cAMP receptor protein (CRP) or the virulence factor regulator (Vfr) modifies the rate of transcription of certain genes, while cAMP binding to ion channels modulates their activity directly. Further studies on cAMP signalling will have important implications, not only for advancing fundamental knowledge but also for identifying targets for the development of new therapeutic agents.
环磷酸腺苷 (cAMP) 在大多数类型的细胞中发挥着关键的调节作用；然而，cAMP 所调控的途径在不同生物和同一生物的不同组织之间可能存在重要差异。cAMP 水平的变化是由多种触发因素引起的，这些因素大多会影响腺苷酸环化酶，即合成 cAMP 的酶。腺苷酸环化酶形成一个庞大而多样化的家族，包括可溶性形式和具有一个或多个跨膜结构域的形式。可溶性腺苷酸环化酶的调节机制涉及与不同蛋白质的相互作用，如发生在大肠杆菌或酵母中，或与钙离子或碳酸氢根离子的相互作用，如发生在哺乳动物细胞中。跨膜环化酶可以被多种蛋白质调节，其中与膜受体偶联的 G 蛋白的α亚基和βγ 复合物是突出的。cAMP 水平还受磷酸二酯酶的活性调节，磷酸二酯酶是水解 cAMP 的酶。磷酸二酯酶可以通过 cAMP、cGMP 或钙离子-钙调蛋白或通过不同的蛋白激酶的磷酸化来调节。通过 cAMP 的调节取决于它与多种蛋白质的结合，即其近端靶标，这反过来又导致各种远端靶标的变化。具体来说，cAMP 与 cAMP 依赖性蛋白激酶 (PKA) 的调节亚基结合会影响 PKA 底物的活性，与 cAMP 直接激活的交换蛋白结合会调节小 GTP 酶，与转录因子如 cAMP 受体蛋白 (CRP) 或毒力因子调节因子 (Vfr) 结合会改变某些基因的转录速率，而 cAMP 与离子通道的结合会直接调节其活性。进一步研究 cAMP 信号将具有重要意义，不仅对推进基础研究知识有意义，而且对确定开发新治疗药物的靶点也有意义。
