The glutamate story
The glutamate story
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DOI：
10.1038/sj.bjp.0706444
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发表时间：
2006-01-01
影响因子：
7.3
通讯作者：
Jane, DE
中科院分区：
文献类型：
--
作者：
Watkins, JC;Jane, DE
从20世纪50年代开始，哺乳动物中枢神经系统中的谷氨酸能突触传递在大约20年的时间里慢慢建立起来。在建立这些受体作为突触递质受体之前，人们意识到谷氨酸和类似氨基酸(统称为兴奋性氨基酸(EAA))通过多个受体介导它们的兴奋作用。EAA受体最初被分为N-甲基-D-天冬氨酸(NMDA)受体和非NMDA受体，后者又细分为Quisquate(后来的AMPA)和Kainate受体，这些受体似乎优先激活这些受体，并根据它们对20世纪70年代逐渐发展起来的一系列不同作用的拮抗剂的敏感性来划分。通过脊髓中某些兴奋通路对一系列特定的NMDA受体拮抗剂的敏感性，明确地表明NMDA受体是脊髓神经元上的突触受体。重要的是，特定的NMDA受体拮抗剂似乎对高级中枢的突触不那么有效。相反，同样阻断非NMDA和NMDA受体的拮抗剂几乎普遍有效地阻断大脑和脊髓内的突触兴奋，证实了非NMDA突触受体系统在整个中枢神经系统中的存在和普遍存在。在20世纪80年代初，NMDA受体被证明参与了几条中枢突触通路，在强烈刺激突触前纤维而影响长时间兴奋性突触后电位的条件下，NMDA受体与非NMDA受体协同作用。NMDA受体的这种激活与非NMDA受体一起导致了长时程增强(LTP)现象，与突触效能(突触可塑性)的持久变化有关，被认为是记忆和学习中的一个重要过程。在20世纪80年代，研究表明，大脑中的某些谷氨酸受体介导了不受NMDA或非NMDA受体拮抗剂影响的生化变化。这种二分法在20世纪90年代初被分子生物学技术解决，发现了两个谷氨酸结合受体蛋白家族(离子亲和型和代谢型受体)。结合特定蛋白亚基的拮抗剂的发展目前使精确识别参与包括突触可塑性在内的一系列中枢突触过程的离散的Iglu或mGlu受体亚型成为可能。
Glutamatergic synaptic transmission in the mammalian central nervous system was slowly established over a period of some 20 years, dating from the 1950s. Realisation that glutamate and like amino acids (collectively known as excitatory amino acids (EAA)) mediated their excitatory actions via multiple receptors preceded establishment of these receptors as synaptic transmitter receptors. EAA receptors were initially classified as N-methyl-D-aspartate (NMDA) and non-NMDA receptors, the latter subdivided into quisqualate (later AMPA) and kainate receptors after agonists that appeared to activate these receptors preferentially, and by their sensitivity to a range of differentially acting antagonists developed progressively during the 1970s. NMDA receptors were definitively shown to be synaptic receptors on spinal neurones by the sensitivity of certain excitatory pathways in the spinal cord to a range of specific NMDA receptor antagonists. Importantly, specific NMDA receptor antagonists appeared to be less effective at synapses in higher centres. In contrast, antagonists that also blocked non-NMDA as well as NMDA receptors were almost universally effective at blocking synaptic excitation within the brain and spinal cord, establishing both the existence and ubiquity of non-NMDA synaptic receptor systems throughout the CNS. In the early 1980s, NMDA receptors were shown to be involved in several central synaptic pathways, acting in concert with non-NMDA receptors under conditions where a protracted excitatory postsynaptic potential was effected in response to intense stimulation of presynaptic fibres. Such activation of NMDA receptors together with non-NMDA receptors led to the phenomenon of long-term potentiation (LTP), associated with lasting changes in synaptic efficacy (synaptic plasticity) and considered to be an important process in memory and learning. During the 1980s, it was shown that certain glutamate receptors in the brain mediated biochemical changes that were not susceptible to NMDA or non-NMDA receptor antagonists. This dichotomy was resolved in the early 1990s by the techniques of molecular biology, which identified two families of glutamate-binding receptor proteins (ionotropic (iGlu) and metabotropic (mGlu) receptors). Development of antagonists binding to specific protein subunits is currently enabling precise identification of discrete iGlu or mGlu receptor subtypes that participate in a range of central synaptic processes, including synaptic plasticity.