Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
Mol Cell Biochem. 2010 Jan;334(1-2):221-32. doi: 10.1007/s11010-009-0318-8. Epub 2009 Dec 11.
The cellular counterpart of the "soluble" guanylyl cyclase found in tissue homogenates over 30 years ago is now recognized as the physiological receptor for nitric oxide (NO). The ligand-binding site is a prosthetic haem group that, when occupied by NO, induces a conformational change in the protein that propagates to the catalytic site, triggering conversion of GTP into cGMP. This review focuses on recent research that takes this basic information forward to the beginnings of a quantitative depiction of NO signal transduction, analogous to that achieved for other major transmitters. At its foundation is an explicit enzyme-linked receptor mechanism for NO-activated guanylyl cyclase that replicates all its main properties. In cells, NO signal transduction is subject to additional, activity-dependent modifications, notably through receptor desensitization and changes in the activity of cGMP-hydrolyzing phosphodiesterases. The measurement of these parameters under varying conditions in rat platelets has made it possible to formulate a cellular model of NO-cGMP signaling. The model helps explain cellular responses to NO and their modification by therapeutic agents acting on the guanylyl cyclase or phosphodiesterase limbs of the pathway.
三十多年前在组织匀浆中发现的“可溶性”鸟苷酸环化酶的细胞对应物现在被认为是一氧化氮（NO）的生理受体。配体结合位点是一个假血红素基团，当被 NO 占据时，会诱导蛋白质发生构象变化，这种变化会传播到催化位点，触发 GTP 转化为 cGMP。本综述重点介绍了将这些基本信息向前推进到定量描述 NO 信号转导的最新研究，类似于对其他主要递质所做的描述。其基础是一个明确的酶联受体机制，用于 NO 激活的鸟苷酸环化酶，该机制复制了其所有主要特性。在细胞中，NO 信号转导会受到额外的、依赖于活性的修饰，特别是通过受体脱敏和 cGMP 水解磷酸二酯酶活性的变化。在不同条件下测量大鼠血小板中的这些参数，使得能够制定一个细胞模型的 NO-cGMP 信号转导。该模型有助于解释细胞对 NO 的反应及其被作用于途径的鸟苷酸环化酶或磷酸二酯酶分支的治疗剂的修饰。
