Diversity and bias through dopamine D2R heteroreceptor complexes
Diversity and bias through dopamine D2R heteroreceptor complexes
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DOI：
10.1016/j.coph.2016.10.004
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发表时间：
2017-02-01
影响因子：
4
通讯作者：
Fuxe, Kjeii
中科院分区：
文献类型：
--
作者：
Borroto-Escuela, Dasiel;Fuxe, Kjeii
D2 R是与大量其他GPCR相互作用的枢纽受体。拮抗性A2 AR-D2 R相互作用的A2 AR活化不仅导致Gi/o信号传导的抑制，而且导致β-抑制蛋白2信号传导超过D2 R原聚体的增加。致幻性5-HT 2AR激动剂可以在D2 R-5-HT 2AR异源受体复合物的5-HT 2AR原聚体处产生偏向激动剂状态，其中D2 R识别和Gi/o介导的信号传导增加。D2-NTR 1异源受体复合物中的变构受体受体相互作用抑制D2 R功能，并可转换G蛋白偶联。这些大量的D2 R杂合物和它们的变构受体-受体相互作用产生参与的D2 R原聚体的多样性和偏差的显著增加，为精神分裂症、成瘾和帕金森病的药物开发开辟了一片乐土。
The D2R is a hub receptor interacting with a large number of other GPCRs. A2AR activation of the antagonistic A2AR-D2R interaction not only leads to inhibition of the Gi/o signaling but also to an increase in beta-arrestin2 signaling over the D2R protomer. Hallucinogenic 5-HT2AR agonists can produce a biased agonist state at the 5-HT2AR protomer of D2R-5-HT2AR heteroreceptor complexes with increased D2R recognition and Gi/o mediated signaling. Allosteric receptor receptor interactions in D2-NTR1 heteroreceptor complexes inhibit D2R function and can switch G protein coupling. These large numbers of D2R heterocomplexes and their allosteric receptor-receptor interactions produce a marked increase in diversity and bias of the participating D2R protomers opening a promised land for drug development in schizophrenia, addiction and Parkinson's disease.