Laboratoire de recherche ophtalmologique, Hôpital Hôtel Dieu, Université Paris 5, 1 place du Parvis, Notre Dame, 75181 Paris cedex 04, France.
Arch Gerontol Geriatr. 2010 Nov-Dec;51(3):260-3. doi: 10.1016/j.archger.2009.11.013. Epub 2009 Dec 14.
The initiation and evolution of the receptor concept and its application in pharmacology can be traced back to Paul Ehrlich's original experiments. Since several decades the receptor concept is in the foreground of cell biology and pharmacology. We present here a short reminder of Ehrlich's concepts on receptor action, its evolution and modifications as a result of increasing life expectancy of human societies. Results obtained by several teams on the age-dependent modifications of receptor function are reviewed with special emphasis on the age-dependent loss of receptors and of uncoupling of receptors from their intracellular transmission pathway. As a special example we summarize our results on the elastin receptor and its age-dependent modifications. These modifications result in the loss of the physiologically helpful functions mediated by this receptor, such as vasodilation by coupling with the inducible nitric oxide synthase (iNOS)-inhibition of cellular cholesterol synthesis and modulation of free radical production by inhibition of the guanine nucleotide binding protein (Gi protein)-mediated transmission pathway. Only the harmful effects such as free radical release and up-regulation of elastase production remain in "old" cells. The age-dependent modifications of receptor function play an important role in the increasing frequency and severity of age-related diseases such as athero-arteriosclerosis and emphysema as well as the loss of hormone- and drug actions. These processes and their inhibition or correction represent a new challenge for cellular pharmacology.
受体概念的起源和发展及其在药理学中的应用可以追溯到保罗·埃尔利希的最初实验。几十年来，受体概念一直是细胞生物学和药理学的前沿。我们在这里简要回顾一下埃尔利希关于受体作用的概念、它的进化以及由于人类社会预期寿命的延长而产生的变化。我们回顾了几个团队关于受体功能随年龄变化的结果，特别强调了受体随年龄的丧失以及受体与其细胞内传递途径的解偶联。作为一个特殊的例子，我们总结了我们关于弹性蛋白受体及其随年龄变化的研究结果。这些变化导致该受体介导的生理有益功能丧失，例如通过与诱导型一氧化氮合酶（iNOS）偶联来扩张血管、抑制细胞胆固醇合成以及通过抑制鸟苷核苷酸结合蛋白（Gi 蛋白）介导的传递途径来调节自由基产生。只有“旧”细胞中的自由基释放和弹性蛋白酶产生增加等有害影响仍然存在。受体功能的年龄相关性变化在动脉粥样硬化和肺气肿等与年龄相关的疾病的频率和严重程度增加以及激素和药物作用丧失中起着重要作用。这些过程及其抑制或纠正代表了细胞药理学的新挑战。
