Adenosine A2A and dopamine D2 heteromeric receptor complexes and their function
Adenosine A2A and dopamine D2 heteromeric receptor complexes and their function
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DOI：
10.1385/jmn:26:2-3:209
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发表时间：
2005-01-01
影响因子：
3.1
通讯作者：
Franco, R
中科院分区：
文献类型：
--
作者：
Fuxe, K;Ferré, S;Franco, R
A(2A)-D-2异质配合物的存在是基于共免疫沉淀研究和荧光共振能量转移和生物发光共振能量转移分析。现在已经有可能证明A（2A）和D-2受体也在纹状体组织中共免疫沉淀，这为A(2A)-D-2异质受体复合物在大鼠纹状体组织中存在提供了证据。分析提供证据表明，这些异构体是组成的，因为它们是在缺乏A（2A）和D-2激动剂的情况下观察到的。A(2A)-D-2异聚体，可以是A(2A)-D-2异聚二聚体和/或高阶A(2A)-D-2异聚物。纹状体神经元中可能存在A(2A)-D-2异质复合物，同时在神经元表面膜中也存在A(2A)-D-2异质复合物。它们在不同微域的化学计量在决定纹状体GABA神经元中的a （2A）和D-2信号传导中起主要作用。通过使用D-2/D-1嵌合体，已经获得证据表明，第五跨膜（TM）结构域和/或D2受体的I3是A(2A)-D-2受体界面的一部分，其中静电表位-表位相互作用涉及D-2受体I3的n端部分（富含精氨酸的表位）起主要作用，与A（2A）受体的羧基端相互作用。A(2A)-D-2异构体的计算机模拟与这些发现一致。A（2A）受体诱导的D-2受体识别、G蛋白偶联和信号传导的减少，以及A(2A)-D-2共运输的存在，似乎可能是A(2A)-D-2受体异聚体存在的结果。强调了A(2A)-D-2异源受体复合物与帕金森病和精神分裂症的相关性以及对这些疾病的治疗。最后，总结了最近在共转染细胞系中存在拮抗A(2A)-D-3异质受体复合物的证据。
The existence of A(2A)-D-2 heteromeric complexes is based on coimmunoprecipitation studies and on fluorescence resonance energy transfer and bioluminescence resonance energy transfer analyses. It has now become possible to show that A(2A) and D-2 receptors also coimmunoprecipitate in striatal tissue, giving evidence for the existence of A(2A)-D-2 heteromeric receptor complexes also in rat striatal tissue. The analysis gives evidence that these heteromers are constitutive, as they are observed in the absence of A(2A) and D-2 agonists. The A(2A)-D-2 heteromers, could either be A(2A)-D-2 heterodimers and/or higher-order A(2A)-D-2 hetero-oligomers. In striatal neurons there are probably A(2A)-D-2 heteromeric complexes, together with A(2A)-D-2 homomeric complexes in the neuronal surface membrane. Their stoichiometry in various microdomains will have a major role in determining A(2A) and D-2 signaling in the striatopallidal GABA neurons. Through the use of D-2/D-1 chimeras, evidence has been obtained that the fifth transmembrane (TM) domain and/or the I3 of the D2 receptor are part of the A(2A)-D-2 receptor interface, where electrostatic epitope-epitope interactions involving the N-terminal part of I3 of the D-2 receptor (arginine-rich epitope) play a major role, interacting with the carboxyl terminus of the A(2A) receptor. Computerized modeling of A(2A)-D-2 heteromers are in line with these findings. It seems likely that A(2A) receptor-induced reduction of D-2 receptor recognition, G protein coupling, and signaling, as well as the existence of A(2A)-D-2 co-trafficking, are the consequence of the existence of an A(2A)-D-2 receptor heteromer. The relevance of A(2A)-D-2 heteromeric receptor complexes for Parkinson's disease and schizophrenia is emphasized as well as for the treatment of these diseases. Finally, recent evidence for the existence of antagonistic A(2A)-D-3 heteromeric receptor complexes in cotransfected cell lines has been summarized.