Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
CNS Neurosci Ther. 2010 Jun;16(3):e18-42. doi: 10.1111/j.1755-5949.2009.00126.x. Epub 2010 Mar 16.
Adenosine-dopamine interactions in the central nervous system (CNS) have been studied for many years in view of their relevance for disorders of the CNS and their treatments. The discovery of adenosine and dopamine receptor containing receptor mosaics (RM, higher-order receptor heteromers) in the striatum opened up a new understanding of these interactions. Initial findings indicated the existence of A(2A)R-D(2)R heterodimers and A(1)R-D(1)R heterodimers in the striatum that were followed by indications for the existence of striatal A(2A)R-D(3)R and A(2A)R-D(4)R heterodimers. Of particular interest was the demonstration that antagonistic allosteric A(2A)-D(2) and A(1)-D(1) receptor-receptor interactions take place in striatal A(2A)R-D(2)R and A(1)R-D(1)R heteromers. As a consequence, additional characterization of these heterodimers led to new aspects on the pathophysiology of Parkinson's disease (PD), schizophrenia, drug addiction, and l-DOPA-induced dyskinesias relevant for their treatments. In fact, A(2A)R antagonists were introduced in the symptomatic treatment of PD in view of the discovery of the antagonistic A(2A)R-D(2)R interaction in the dorsal striatum that leads to reduced D(2)R recognition and G(i/o) coupling in striato-pallidal GABAergic neurons. In recent years, indications have been obtained that A(2A)R-D(2)R and A(1)R-D(1)R heteromers do not exist as heterodimers, rather as RM. In fact, A(2A)-CB(1)-D(2) RM and A(2A)-D(2)-mGlu(5) RM have been discovered using a sequential BRET-FRET technique and by using the BRET technique in combination with bimolecular fluorescence complementation. Thus, other pathogenic mechanisms beside the well-known alterations in the release and/or decoding of dopamine in the basal ganglia and limbic system are involved in PD, schizophrenia and drug addiction. In fact, alterations in the stoichiometry and/or topology of A(2A)-CB(1)-D(2) and A(2A)-D(2)-mGlu5 RM may play a role. Thus, the integrative receptor-receptor interactions in these RM give novel aspects on the pathophysiology and treatment strategies, based on combined treatments, for PD, schizophrenia, and drug addiction.
中枢神经系统（CNS）中的腺苷-多巴胺相互作用多年来一直受到关注，因为它们与 CNS 疾病及其治疗有关。纹状体中发现含有受体镶嵌物（RM，更高阶受体异源二聚体）的腺苷和多巴胺受体为这些相互作用提供了新的认识。最初的发现表明，纹状体中存在 A(2A)R-D(2)R 异二聚体和 A(1)R-D(1)R 异二聚体，随后表明纹状体中存在 A(2A)R-D(3)R 和 A(2A)R-D(4)R 异二聚体。特别有趣的是，证明在纹状体的 A(2A)R-D(2)R 和 A(1)R-D(1)R 异源二聚体中存在拮抗变构的 A(2A)-D(2)和 A(1)-D(1)受体-受体相互作用。因此，对这些异源二聚体的进一步表征导致了帕金森病（PD）、精神分裂症、药物成瘾和与 l-DOPA 诱导的运动障碍相关的新的病理生理学方面，这些疾病与它们的治疗有关。事实上，鉴于在背侧纹状体中发现了拮抗的 A(2A)R-D(2)R 相互作用，导致纹状体-苍白球 GABA 能神经元中 D(2)R 识别和 G(i/o)偶联减少，A(2A)R 拮抗剂被引入 PD 的症状治疗中。近年来，已经有迹象表明，A(2A)R-D(2)R 和 A(1)R-D(1)R 异源二聚体不作为异二聚体存在，而是作为 RM。事实上，已经使用顺序 BRET-FRET 技术和 BRET 技术与双分子荧光互补相结合发现了 A(2A)-CB(1)-D(2)RM 和 A(2A)-D(2)-mGlu(5)RM。因此，除了基底神经节和边缘系统中多巴胺释放和/或解码的众所周知的改变之外，其他致病机制也与 PD、精神分裂症和药物成瘾有关。事实上，A(2A)-CB(1)-D(2)和 A(2A)-D(2)-mGlu5 RM 的化学计量和/或拓扑的改变可能起作用。因此，这些 RM 中的整合受体-受体相互作用为 PD、精神分裂症和药物成瘾提供了基于联合治疗的病理生理学和治疗策略的新方面。
