Dopamine D2-D3 receptor heteromers: pharmacological properties and therapeutic significance
Dopamine D2-D3 receptor heteromers: pharmacological properties and therapeutic significance
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DOI：
10.1016/j.coph.2009.10.001
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发表时间：
2010-02-01
影响因子：
4
通讯作者：
Millan, Mark J.
中科院分区：
文献类型：
--
作者：
Maggio, Roberto;Millan, Mark J.
多巴胺受体的异聚化已经显示为D-1/D-5和D-2/D-3/D-4受体家族，它们分别与腺苷酸环化酶正性和负性偶联。本文综述了由D-3形成的多巴胺异聚体的数据，特别关注与D-2对应物的关联。某些抗帕金森病药物，如优先和高效的D-3 > D-2激动剂、普拉克索和罗匹尼罗，在D-2-D-3异聚体相对于组成单体显示出放大的效力。因此，在用D-2和D-3受体共转染的细胞中，与仅用D-2或D-3受体转染的细胞相比，普拉克索和罗匹尼罗以更高的效力抑制毛喉素（FK）刺激的cAMP产生。此外，在用D-2和过量D-3受体共转染的细胞中，部分激动剂阿立哌唑、S33592、联苯芦诺、N-去甲基氯氮平和普瑞拉莫失去激动剂性质并消除了奎吡罗的作用。然后，在D-2与过量的D-3受体共转染后，部分激动剂转化为拮抗剂。上述观察的病理生理学和可能的治疗神经精神疾病的假设关系进行了讨论。
Heteromerization of dopamine receptors has been shown for both the D-1/D-5 and D-2/D-3/D-4 receptor families, which couple positively and negatively, respectively, to adenylyl cyclase. The present article reviews data on dopamine heteromers formed by D-3, focusing in particular on associations with their D-2 counterparts. Certain antiparkinsonian agents, like the preferential and high efficacy D-3 > D-2 agonists, pramipexole, and ropinirole, show amplified potency at D-2-D-3 heteromers versus constituent monomers. Accordingly, in cells cotransfected with D-2 and D-3 receptors, pramipexole, and ropinirole suppress forskolin (FK)-stimulated cAMP production with higher potencies as compared to cells transfected with D-2 or D-3 receptors only. Furthermore, in cells cotransfected with D-2 and an excess of D-3 receptors, the partial agonists aripiprazole, S33592, bifeprunox, N-desmethylclozapine, and preclamol lose agonist properties and abolish the actions of quinpirole. Then, partial agonists are transformed into antagonists upon cotransfection of D-2 with an excess of D-3 receptors. A hypothetical relationship of the above observations to the pathophysiology and possibly treatment of neuropsychiatric diseases is discussed.