Woodward Hopf F, Mangieri Regina A
Alcohol Center for Translational Genetics, Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA.
Handb Exp Pharmacol. 2018;248:157-186. doi: 10.1007/164_2018_105.
Ionotropic glutamate receptors (AMPA, NMDA, and kainate receptors) play a central role in excitatory glutamatergic signaling throughout the brain. As a result, functional changes, especially long-lasting forms of plasticity, have the potential to profoundly alter neuronal function and the expression of adaptive and pathological behaviors. Thus, alcohol-related adaptations in ionotropic glutamate receptors are of great interest, since they could promote excessive alcohol consumption, even after long-term abstinence. Alcohol- and drug-related adaptations in NMDARs have been recently reviewed, while less is known about kainate receptor adaptations. Thus, we focus here on functional changes in AMPARs, tetramers composed of GluA1-4 subunits. Long-lasting increases or decreases in AMPAR function, the so-called long-term potentiation or depression, have widely been considered to contribute to normal and pathological memory states. In addition, a great deal has been learned about the acute regulation of AMPARs by signaling pathways, scaffolding and auxiliary proteins, intracellular trafficking, and other mechanisms. One important common adaptation is a shift in AMPAR subunit composition from GluA2-containing, calcium-impermeable AMPARs (CIARs) to GluA2-lacking, calcium-permeable AMPARs (CPARs), which is observed under a broad range of conditions including intoxicant exposure or intake, stress, novelty, food deprivation, and ischemia. This shift has the potential to facilitate AMPAR currents, since CPARs have much greater single-channel currents than CIARs, as well as faster AMPAR activation kinetics (although with faster inactivation) and calcium-related activity. Many tools have been developed to interrogate particular aspects of AMPAR signaling, including compounds that selectively inhibit CPARs, raising exciting translational possibilities. In addition, recent studies have used transgenic animals and/or optogenetics to identify AMPAR adaptations in particular cell types and glutamatergic projections, which will provide critical information about the specific circuits that CPARs act within. Also, less is known about the specific nature of alcohol-related AMPAR adaptations, and thus we use other examples that illustrate more fully how particular AMPAR changes might influence intoxicant-related behavior. Thus, by identifying alcohol-related AMPAR adaptations, the specific molecular events that underlie them, and the cells and projections in which they occur, we hope to better inform the development of new therapeutic interventions for addiction.
离子型谷氨酸受体（AMPA、NMDA和海人藻酸受体）在整个大脑的兴奋性谷氨酸能信号传导中起着核心作用。因此，功能变化，尤其是长期形式的可塑性，有可能深刻改变神经元功能以及适应性和病理行为的表达。因此，离子型谷氨酸受体中与酒精相关的适应性变化备受关注，因为它们可能导致过度饮酒，即使在长期戒酒之后也是如此。最近已有关于NMDARs中与酒精和药物相关的适应性变化的综述，而对于海人藻酸受体的适应性变化了解较少。因此，我们在此聚焦于由GluA1 - 4亚基组成的四聚体AMPARs的功能变化。AMPAR功能的长期增加或减少，即所谓的长期增强或抑制，已被广泛认为与正常和病理记忆状态有关。此外，关于信号通路、支架蛋白和辅助蛋白、细胞内运输及其他机制对AMPARs的急性调节，我们也有了很多了解。一种重要的常见适应性变化是AMPAR亚基组成从含GluA2的、钙不透性AMPARs（CIARs）向缺乏GluA2的、钙通透性AMPARs（CPARs）的转变，这种转变在包括接触或摄入毒物、应激、新奇环境、食物剥夺和缺血等广泛条件下都能观察到。这种转变有可能促进AMPAR电流，因为CPARs的单通道电流比CIARs大得多，并且具有更快的AMPAR激活动力学（尽管失活更快）以及与钙相关的活性。已经开发出许多工具来探究AMPAR信号传导的特定方面，包括选择性抑制CPARs的化合物，这带来了令人兴奋的转化可能性。此外，最近的研究使用转基因动物和/或光遗传学来识别特定细胞类型和谷氨酸能投射中的AMPAR适应性变化，这将提供关于CPARs起作用的特定回路的关键信息。而且，对于与酒精相关的AMPAR适应性变化的具体性质了解较少，因此我们使用其他例子来更全面地说明特定的AMPAR变化可能如何影响与毒物相关的行为。因此，通过识别与酒精相关的AMPAR适应性变化、其背后的特定分子事件以及发生这些变化的细胞和投射，我们希望能更好地为成瘾新治疗干预措施的开发提供信息。
