Trace amine-associated receptor 1 activation silences GSK3β signaling of TAAR1 and D2R heteromers
Trace amine-associated receptor 1 activation silences GSK3β signaling of TAAR1 and D2R heteromers
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DOI：
10.1016/j.euroneuro.2015.08.011
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发表时间：
2015-11-01
影响因子：
5.6
通讯作者：
Hoener, Marius C.
中科院分区：
文献类型：
--
作者：
Harmeier, Anja;Obermueller, Stefan;Hoener, Marius C.
选择性内源性激动剂激活微量胺相关受体1 （TAAR1）可调节多巴胺能神经传递。这导致体内抗精神病样行为，这可能是由TAAR1和多巴胺D2L受体（D2R）相互作用启动的。在这里，我们使用高效和选择性的TAAR1激动剂，以及新产生的工具，如TAAR1敲除和TAAR1过表达大鼠以及特异性抗大鼠TAAR1抗体，分析了TAAR1和D2R之间的功能联系。我们提供了来自共免疫沉淀实验的数据，支持两种受体在异源细胞和脑组织中的功能相互作用。TAAR1与D2R的相互作用改变了TAAR1的亚细胞定位，增加了D2R激动剂的结合亲和力。通过特异性β -抑制蛋白2 （β - Arr2）互补实验，我们发现TAAR1与D2R的相互作用减少了β - Arr2向D2R的募集。此外，我们报道，除了气体蛋白信号，TAAR1也通过β Arr2信号。在D2R的存在下，TAAR1的cAMP信号传导减少，而其β Arr2信号传导增强，导致GSK3 β激活减少。这些结果表明β - Arr2信号通路可能是TAAR1功能的重要途径，TAAR1- d2r复合物的激活可负向调节GSK3 β信号通路。鉴于精神分裂症或双相情感障碍患者表现出GSK3 β信号的增加，这种由D2R与活化的TAAR1相互作用引发的GSK3 β信号的减少进一步支持了TAAR1作为治疗精神疾病的靶点。(C) 2015 Elsevier B.V.和ECNP。版权所有。
Trace amine-associated receptor 1 (TAAR1) activation by selective endogenous agonists modulates dopaminergic neurotransmission. This results in antipsychotic-like behavior in vivo which might be initiated by an interaction of TAAR1 and dopamine D2L receptor (D2R). Here we analyzed the functional link between TAAR1 and D2R using highly potent and selective TAAR1 agonists, and newly generated tools such as TAAR1 knock-out and TAAR1 overexpressing rats as well as specific anti-rat TAAR1 antibodies. We provide data from co-immunoprecipitation experiments supporting a functional interaction of the two receptors in heterologous cells and in brain tissue. Interaction of TAAR1 with D2R altered the subcellular localization of TAAR1 and increased D2R agonist binding affinity. Using specific beta-arrestin 2 ((beta Arr2) complementation assays we show that the interaction of TAAR1 with D2R reduced beta Arr2 recruitment to D2R. In addition, we report that besides Gas-protein signaling TAAR1 also signals via beta Arr2. In the presence of D2R, cAMP signaling of TAAR1 was reduced while its beta Arr2 signaling was enhanced, resulting in reduced GSK3 beta activation. These results demonstrate that beta Arr2 signaling may be an important pathway for TAAR1 function and that the activation of the TAAR1-D2R complex negatively modulates GSK3 beta signaling. Given that patients with schizophrenia or bipolar disorder show increased GSK3 beta signaling, such a reduction of GSK3 beta signaling triggered by the interaction of D2R with activated TAAR1 further supports TAAR1 as a target for the treatment of psychiatric disorders. (C) 2015 Elsevier B.V. and ECNP. All rights reserved.