Understanding the Role of GPCR Heteroreceptor Complexes in Modulating the Brain Networks in Health and Disease.
Understanding the Role of GPCR Heteroreceptor Complexes in Modulating the Brain Networks in Health and Disease.
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DOI：
10.3389/fncel.2017.00037
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发表时间：
2017
影响因子：
5.3
通讯作者：
Fuxe K
中科院分区：
文献类型：
--
作者：
Borroto-Escuela DO;Carlsson J;Ambrogini P;Narváez M;Wydra K;Tarakanov AO;Li X;Millón C;Ferraro L;Cuppini R;Tanganelli S;Liu F;Filip M;Diaz-Cabiale Z;Fuxe K
在中枢神经系统（CNS）的G蛋白偶联受体（GPCR）异源受体复合物中引入变构受体-受体相互作用，为脑整合和神经精神药理学提供了新的维度。学习和记忆的分子基础被认为是基于突触连接后膜中同种和异种受体复合物的重组。长期记忆可以通过将异源受体复合物的一部分转化为独特的转录因子来产生，所述转录因子可以导致特异性衔接蛋白的形成。对GPCR异二聚体网络（GPCR-HetNet）的观察表明，变构受体-受体相互作用显著增加GPCR多样性，并且偏向识别和信号传导，导致信号传导的特异性增强。GPCR异源受体复合物的功能障碍可导致脑部疾病。在过去的十年中，大脑中5-羟色胺（5-HT）异源和异源受体复合物的发现为抑郁症的药物开发提供了新的靶点。通过5-HT、甘丙肽和锌对抑郁症神经元网络的神经调节涉及中缝-海马系统中的许多GPCR异源受体复合物：GalR 1 -5-HT 1A、GalR 1 -5-HT 1A-GPR 39、GalR 1-GalR 2和推定的GalR 1-GalR 2 -5-HT 1A异源受体复合物。5-HT 1A受体原聚体通过参与上述相互平衡的异源和同源受体复合物而保持为增强抗抑郁作用的受体。在抑郁症中，通过5-HT和成纤维细胞生长因子2对中缝-海马系统和皮质区域的神经元网络的神经调节涉及FGFR 1 -5-HT 1A异源受体复合物或5-HT同种受体复合物，如5-HT 1A-5-HT 7和5-HT 1A-5-HT 2A。通过多巴胺（DA）和腺苷信号对可卡因使用障碍中的神经元网络的神经调节涉及背侧和腹侧纹状体中的A2 AR-D2 R和A2 AR-D2 R-Sigma 1 R异源受体复合物。A2 AR激动剂通过靶向A2 AR-D2 R和A2 AR-D2 R-Sigma 1 R异源受体复合物对腹侧纹状体-苍白球GABA抗奖赏系统的兴奋性调节作为治疗可卡因使用障碍的新方法具有很高的前景。通过DA、腺苷、谷氨酸、5-HT和神经降压肽和催产素对精神分裂症中的神经元网络进行神经调节，涉及A2 AR-D2 R、D2 R-NMDAR、A2 AR-D2 R-mGluR 5、D2 R-5-HT 2A和D2 R-催产素R异源受体复合物，开辟了所列异源复合物中D2 R原异构体靶点的新世界，用于治疗精神分裂症的阳性、阴性和认知症状。
The introduction of allosteric receptor–receptor interactions in G protein-coupled receptor (GPCR) heteroreceptor complexes of the central nervous system (CNS) gave a new dimension to brain integration and neuropsychopharmacology. The molecular basis of learning and memory was proposed to be based on the reorganization of the homo- and heteroreceptor complexes in the postjunctional membrane of synapses. Long-term memory may be created by the transformation of parts of the heteroreceptor complexes into unique transcription factors which can lead to the formation of specific adapter proteins. The observation of the GPCR heterodimer network (GPCR-HetNet) indicated that the allosteric receptor–receptor interactions dramatically increase GPCR diversity and biased recognition and signaling leading to enhanced specificity in signaling. Dysfunction of the GPCR heteroreceptor complexes can lead to brain disease. The findings of serotonin (5-HT) hetero and isoreceptor complexes in the brain over the last decade give new targets for drug development in major depression. Neuromodulation of neuronal networks in depression via 5-HT, galanin peptides and zinc involve a number of GPCR heteroreceptor complexes in the raphe-hippocampal system: GalR1-5-HT1A, GalR1-5-HT1A-GPR39, GalR1-GalR2, and putative GalR1-GalR2-5-HT1A heteroreceptor complexes. The 5-HT1A receptor protomer remains a receptor enhancing antidepressant actions through its participation in hetero- and homoreceptor complexes listed above in balance with each other. In depression, neuromodulation of neuronal networks in the raphe-hippocampal system and the cortical regions via 5-HT and fibroblast growth factor 2 involves either FGFR1-5-HT1A heteroreceptor complexes or the 5-HT isoreceptor complexes such as 5-HT1A-5-HT7 and 5-HT1A-5-HT2A. Neuromodulation of neuronal networks in cocaine use disorder via dopamine (DA) and adenosine signals involve A2AR-D2R and A2AR-D2R-Sigma1R heteroreceptor complexes in the dorsal and ventral striatum. The excitatory modulation by A2AR agonists of the ventral striato-pallidal GABA anti-reward system via targeting the A2AR-D2R and A2AR-D2R-Sigma1R heteroreceptor complex holds high promise as a new way to treat cocaine use disorders. Neuromodulation of neuronal networks in schizophrenia via DA, adenosine, glutamate, 5-HT and neurotensin peptides and oxytocin, involving A2AR-D2R, D2R-NMDAR, A2AR-D2R-mGluR5, D2R-5-HT2A and D2R-oxytocinR heteroreceptor complexes opens up a new world of D2R protomer targets in the listed heterocomplexes for treatment of positive, negative and cognitive symptoms of schizophrenia.