Fuxe K, Ferré S, Zoli M, Agnati L F
Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
Brain Res Brain Res Rev. 1998 May;26(2-3):258-73. doi: 10.1016/s0165-0173(97)00049-0.
An analysis at the network and membrane level has provided evidence that antagonistic interactions between adenosine A2A/dopamine D2 and adenosine A1/dopamine D1 receptors in the ventral and dorsal striatum are at least in part responsible for the motor stimulant effects of adenosine receptor antagonists like caffeine and for the motor depressant actions of adenosine receptor agonists. The results obtained in stably cotransfected cells also underline the hypothesis that the intramembrane A2A/D2 and A1/D1 receptor interactions represent functionally important mechanisms that may be the major mechanism for the demonstrated antagonistic A2A/D2 and A1/D1 receptor interactions found in vivo in behavioural studies and in studies on in vivo microdialysis of the striopallidal and strioentopeduncular GABAergic pathways. A major mechanism for the direct intramembrane A2A/D2 and A1/D1 receptor interactions may involve formation of A2A/D2 and A1/D1 heterodimers leading to allosteric changes that will alter the affinity as well as the G protein coupling and thus the efficacy to control the target proteins in the membranes. This is the first molecular network to cellular integration in the nerve cell membrane and may be well suited for a number of integrated tasks and can be performed in a short-time scale, in comparison with the very long-time scale observed when receptor heteroregulation involves phosphorylation or receptor resynthesis. Multiple receptor-receptor interactions within the membranes through formation of receptor clusters may lead to the storage of information within the membranes. Such molecular circuits can represent hidden layers within the membranes that substantially increase the computational potential of neuronal networks. These molecular circuits are biased and may therefore represent part of the molecular mechanism for the storage of memory traces (engrams) in the membranes.
在网络和膜水平上的分析已提供证据表明，腹侧和背侧纹状体中腺苷A2A/多巴胺D2以及腺苷A1/多巴胺D1受体之间的拮抗相互作用至少部分地导致了咖啡因等腺苷受体拮抗剂的运动兴奋作用以及腺苷受体激动剂的运动抑制作用。在稳定共转染细胞中获得的结果也强调了这样一种假设，即膜内A2A/D2和A1/D1受体相互作用代表了功能上重要的机制，这可能是行为研究以及纹状体苍白球和纹状体脑桥脚内核GABA能通路的体内微透析研究中所证实的体内A2A/D2和A1/D1受体拮抗相互作用的主要机制。膜内A2A/D2和A1/D1受体直接相互作用的一个主要机制可能涉及A2A/D2和A1/D1异二聚体的形成，从而导致变构变化，这将改变亲和力以及G蛋白偶联，进而改变控制膜中靶蛋白的效力。这是神经细胞膜中第一个从分子网络到细胞整合的过程，与受体异调节涉及磷酸化或受体再合成时观察到的非常长的时间尺度相比，它可能非常适合许多整合任务，并且可以在短时间内完成。膜内通过形成受体簇的多个受体-受体相互作用可能导致信息在膜内的存储。这样的分子回路可以代表膜内的隐藏层，从而大大增加神经网络的计算潜力。这些分子回路具有偏向性，因此可能代表了膜中记忆痕迹（记忆印记）存储的分子机制的一部分。
