Gispen W H
Rudolf Magnus Instituut voor Neurowetenschappen, afd. Medische Farmacologie, Universiteit Utrecht.
Ned Tijdschr Geneeskd. 2000 Nov 11;144(46):2184-7.
The three Nobel laureates Arvid Carlsson, Paul Greengard and Eric Kandel have made pioneering discoveries concerning slow synaptic transmission between neurons. As common theme, for which the Nobel Prize in Physiology or Medicine for 2000 is given, the Nobel Assembly chose 'signal transduction in the nervous system'. The work of Carlsson led to the discovery of dopamine as transmitter in the brain and opened the way for the development of the levodopa therapy of patients suffering from Parkinson's disease. His later work concentrated on the dopamine hypothesis of schizophrenia and the rationale for the mechanism of action of antipsychotics. Greengard pioneered the field of receptor-mediated phosphorylation and dephosphorylation of brain proteins. He was the first to describe the cyclic-AMP-dependent protein kinase in the brain and the activation of this kinase following dopamine receptor activation. A substrate enriched in cells that bear dopamine receptors is 'dopamine- and cyclic-AMP-regulated phosphoprotein' (DARPP-32). Phosphorylation by the cyclic-AMP-dependent kinase influences its protein phosphatase inhibiting capacity and, as such, DARPP-32 is an important 'feed-forward activator' in the dopamine signal transduction cascade. Kandel received the prize for his contributions to our understanding of the neural substrate of learning and memory. Most of his work was carried out in the sea slug Aplysia in which he was able to relate three psychologically defined forms of learning--habituation, sensitisation, and classical conditioning--to subcellular processes and intercellular signalling. Kandel is known all over the world for his eminent textbook Principles of Neural Science which inspired generations of young neuroscientists. It seems that it is not so much the signal transduction that joins these laureates but their outstanding conceptual approach to, in fact, three different themes of the neurosciences during the second part of the last century.
三位诺贝尔奖获得者阿尔维德·卡尔森、保罗·格林加德和埃里克·坎德尔在神经元之间缓慢突触传递方面做出了开创性发现。作为共同主题，诺贝尔大会将2000年诺贝尔生理学或医学奖授予“神经系统中的信号转导”。卡尔森的研究发现了多巴胺作为大脑中的神经递质，为帕金森病患者左旋多巴疗法的发展开辟了道路。他后来的工作集中在精神分裂症的多巴胺假说以及抗精神病药物作用机制的理论基础上。格林加德开创了受体介导的脑蛋白磷酸化和去磷酸化领域。他是第一个描述大脑中依赖环磷酸腺苷的蛋白激酶以及多巴胺受体激活后该激酶的激活情况的人。富含多巴胺受体的细胞中的一种底物是“多巴胺和环磷酸腺苷调节的磷蛋白”（DARPP - 32）。依赖环磷酸腺苷的激酶的磷酸化会影响其蛋白磷酸酶抑制能力，因此，DARPP - 32是多巴胺信号转导级联中的一个重要“前馈激活剂 ”。坎德尔因其对我们理解学习和记忆的神经基础所做的贡献而获奖。他的大部分工作是在海兔中进行的，在那里他能够将三种心理学定义的学习形式——习惯化、敏感化和经典条件反射——与亚细胞过程和细胞间信号传导联系起来。坎德尔因其杰出的教科书《神经科学原理》而闻名于世，这本书激励了一代又一代年轻的神经科学家。似乎将这些获奖者联系在一起的与其说是信号转导，不如说是他们在上个世纪后半叶对神经科学三个不同主题所采用的杰出概念方法。
