Signaling in dopamine D2 receptor-oxytocin receptor heterocomplexes and its relevance for the anxiolytic effects of dopamine and oxytocin interactions in the amygdala of the rat
Signaling in dopamine D2 receptor-oxytocin receptor heterocomplexes and its relevance for the anxiolytic effects of dopamine and oxytocin interactions in the amygdala of the rat
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DOI：
10.1016/j.bbadis.2016.07.004
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发表时间：
2016-11-01
影响因子：
6.2
通讯作者：
Borroto-Escuela, Dasiel O.
中科院分区：
文献类型：
--
作者：
Perez de la Mora, Miguel;Perez-Carrera, Diana;Borroto-Escuela, Dasiel O.
多巴胺D2受体（D2 R）-催产素受体（OTR）相互作用存在于杂合物中，对D2 R识别和Gi/o偶联具有易化作用。在这项工作中，使用共转染的HEK 293细胞的假设进行了测试，变构相互D2 R-OTR的相互作用是否可以增强信号的D2 R-OTR杂合物沿着CREB，MAPK和PLC途径，以及是否OT的抗焦虑作用可能涉及中央杏仁核（CeA）内的D2 R-OTR相互作用的促进。催产素增强了D2样激动剂喹吡罗诱导的AC-PKA-pCREB信号级联的抑制，并增加了其在RAS-MAPK-pELK通路上的信号传导。喹吡罗增强了催产素诱导的PLC β-IP 3-钙调磷酸酶和RAS-MAPK-pELK级联反应活性的增加。双侧催产素（0.9-150 ng/侧）输注到大鼠的CeA中，在电击探针埋藏试验（一种无条件的恐惧/焦虑模型）中引起抗焦虑作用。当催产素（25 ng/侧）与雷氯必利（250或500 ng/侧）（一种D2/D3拮抗剂）同时共同输注到CeA时，未观察到这种作用。根据目前的研究结果，阻断催产素的抗焦虑作用的同时内CeA管理的雷氯必利可以解释为缺乏促进原异构体相互作用的D2 R-OTR杂合物。中央杏仁核中这种相互作用的功能障碍和/或破坏可能导致焦虑的发展。这种相互作用的恢复可能代表了一种新的抗焦虑药物开发的新策略。(C)© 2016 Elsevier B. V.版权所有。
Dopamine D2 receptor (D2R)-oxytocin receptor (OTR) interactions exist within heterocomplexes with facilitatory effects on D2R recognition and Gi/o coupling. In this work the hypothesis is tested using cotransfected HEK293 cells whether allosteric reciprocal D2R-OTR interactions can enhance signaling of D2R-OTR heterocomplexes along the CREB, MAPK and PLC pathways and whether the anxiolytic effects of OT may involve facilitatory D2R-OTR interactions within the central amygdaloid nucleus (CeA). Oxytocin enhanced the D2-like agonist quinpirole induced inhibition of the AC-PKA-pCREB signaling cascade and increased its signaling over the RAS-MAPK-pELK pathway. Quinpirole enhanced the oxytocin induced increases in the activity of the PLCbeta-IP3-calcineurin and RAS-MAPK-pELK cascades. Bilateral infusion of oxytocin (0.9-150 ng/side) into the CeA of the rat elicited anxiolytic effects in the Shock-Probe Burying test, an unconditioned model of fear/anxiety. This action was not observed when oxytocin (25 ng/side) was simultaneously co-infused with raclopride (neither 250 nor 500 ng/side), a D2/D3 antagonist, into the CeA. Based on the current findings, the blockade of the anxiolytic effects of oxytocin by the simultaneous intra-CeA administration of raclopride can be explained by a lack of facilitatory protomer interactions in D2R-OTR heterocomplexes. Dysfunction and/or disruption of such interactions in the central amygdala may lead to anxiety development. Restoration of such interactions may represent a new strategy for development of novel anxiolytic drugs. (C) 2016 Elsevier B.V. All rights reserved.