Functional consequences of changes in NMDA receptor subunit expression during development
Functional consequences of changes in NMDA receptor subunit expression during development
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DOI：
10.1007/bf02284847
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发表时间：
1996-12-01
期刊：
影响因子：
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通讯作者：
CullCandy, S
中科院分区：
文献类型：
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作者：
Feldmeyer, D;CullCandy, S
氨基酸谷氨酸是介导CNS中快速兴奋性突触反应的主要神经递质。离子型谷氨酸受体具有允许阳离子流入突触后细胞的完整离子通道，因此是参与在许多中枢突触产生去极化信号的基本元件。根据药理学和分子生物学研究，谷氨酸受体分为N-甲基-D-天冬氨酸（NMDA）和非NMDA受体。非NMDA受体组进一步细分为AMPA（左旋丙酸盐）和红藻氨酸盐亚型（根据优先激活它们的激动剂命名）。分子克隆揭示了构成这些受体的亚基的相当大的多样性。因此，亚基可能存在于由选择性剪接和（在一些非NMDA受体的情况下）RNA编辑产生的不同同种型中（由Hollmann和Heinemann，1994; Seeburg，1996综述）。此外，一个家族内的各种亚基可以共组装形成具有显著不同性质（动力学、单通道电导和药理学特征）的寡聚复合物。有关单个细胞内亚基互补（或存在的亚基mRNA）的可用信息量不断增加，为了解谷氨酸受体的亚基组成提供了额外的刺激。图1显示了NMDA受体亚基mRNA在小脑主要细胞类型中的分布，我们将在本文中重点关注小脑区域。有关mRNA的信息提供了有关受体群体中可能涉及的亚基的有价值的线索，尽管这种关系由于单个细胞中可能存在不止一种类型的NMDA或非NMDA受体而变得复杂。早期的工作表明，AMPA和NMDA受体都可以被突触前末端释放的单个谷氨酸包激活，这表明这些受体可能共定位于突触后膜中并且可接近间隙中的递质（Bekkers和Stevens，1989;银等人，1992年）。这种情况似乎比最初认识到的更复杂，有证据表明某些区域的突触受体分布不均匀，并且存在一些缺乏快速非NMDA成分的“沉默”突触。然而，在许多突触谷氨酸介导的兴奋性突触后电流（EPSC）表现出两个不同的组件，反映了显着的差异，无论是在单通道特性和AMPA和NMDA受体的亲和力。在图2所示的例子中，小脑苔藓纤维-颗粒细胞突触处EPSC的快速成分由AMPA型受体介导。在竞争性NMDA受体拮抗剂APV（D-氨基膦戊酸酯;图2A）的存在下，可以看到非NMDA组分快速上升（100-200 μ s）并以约-1 ms的时间常数衰减（尽管这通过两个指数组分更好地描述;参见银et al.，1996年）。根据细胞类型，AMPA受体EPSC的衰减时间常数范围为-1-8ms（参见Jonas & Burnashev，1995）。该事件的快速时间过程使其很好地适应高频突触传递而不丢失时间信息，其方式类似于终板电流（参见Katz & Miledi，1969）。另一方面，NMDA受体组分显示出通常与离子型受体无关的性质。它的崛起
The amino acid glutamate is the principal neurotransmitter mediating fast excitatory synaptic responses in the CNS. Ionotropic glutamate receptors have an integral ion channel allowing an influx of cations into the postsynaptic cell, and are therefore the basic elements involved in producing the depolarizing signal at many central synapses. Based on pharmacological and molecular biological studies glutamate receptors have been divided into N-methyl-D-aspartate (NMDA) and non-NMDA receptors. The non-NMDA receptor group has been further subdivided into AMPA (r lepropionate) and kainate subtypes (named according to the agonists which preferentially activate them). Molecular cloning has revealed considerable diversity in the subunits constituting these receptors. Thus subunits may exist in different isoforms arising from alternative splicing, and (in the case of some non-NMDA receptors) RNA editing (reviewed by Hollmann & Heinemann, 1994; Seeburg, 1996). Furthermore, the various subunits within a family can coassemble to form oligomeric complexes with remarkably different properties (kinetics, single-channel conductance and pharmacological characteristics). The increasing amount of information available about the subunit complement (or subunit mRNAs present) within individual cells has provided an added stimulus to understanding the subunit composition of glutamate receptors. Figure 1 illustrates the distribution of NMDA receptor subunit mRNAs expressed in the main cell types of the cerebellumthe brain region that we will focus on in this article. Information about the mRNAs present gives valuable clues about the possible subunits involved in the receptor population, although the relationship is complicated by the fact that more than one type of NMDA or non-NMDA receptor can be present within individual cells.Early work indicated that both AMPA and NMDA receptors can be activated by a single packet of glutamate released from the presynaptic terminal, suggesting that these receptors may be co-localized in the postsynaptic membrane and accessible to transmitter in the cleft (Bekkers & Stevens, 1989; Silver et al., 1992). The situation appears to be more complex than was initially realized with evidence for the nonuniform distribution of synaptic receptors in some regions, and the presence of some'silent'synapses lacking in the fast non-NMDA component. However, at many synapses the glutamate mediated excitatory postsynaptic currents (EPSCs) exhibit two distinct components, reflecting the marked differences both in single channel properties and in the affinity of AMPA and NMDA receptors. In the example illustrated in Fig. 2, the fast component of the EPSC at the mossy fibre-granule cell synapse in the cerebellum is mediated by AMPA-type receptors. In the presence of the competitive NMDA receptor antagonist APV (D-aminophosphono-valerate; Fig. 2A) the non-NMDA component can be seen to rise rapidly (100-200~ ts) and decay with a time constant of about-1 ms (although this is better described by two exponential components; see Silver et al., 1996). Depending on the cell type the decay time constants of the AMPA receptor EPSC range from-1-8ms (see Jonas & Burnashev, 1995). The fast time course of this event makes it well adapted to high frequency synaptic transmission without loss of temporal information, in a fashion similar to that of the endplate current (see Katz & Miledi, 1969). On the other hand, the NMDA receptor component shows properties not usually associated with ionotropic receptors. Both its rise