Signaling transduction regulated by 5-hydroxytryptamine 1A receptor and orexin receptor 2 heterodimers.
Signaling transduction regulated by 5-hydroxytryptamine 1A receptor and orexin receptor 2 heterodimers.
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DOI：
10.1016/j.cellsig.2018.11.014
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发表时间：
2019-02
影响因子：
4.8
通讯作者：
Qinqin Wang;Chunmei Wang;Bao-hua Cheng;Chunqing Yang;Bo Bai;J. Chen
中科院分区：
文献类型：
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作者：
Qinqin Wang;Chunmei Wang;Bao-hua Cheng;Chunqing Yang;Bo Bai;J. Chen
作为g蛋白偶联受体（gpcr）， 5-羟色胺1A受体（5-HT1AR）和食欲素受体2 （OX2R）调节细胞下游分子的水平。不同gpcr的异源二聚体在多种神经系统疾病中发挥着重要作用。此外，5-HT1AR和OX2R还参与抑郁症等海马可塑性不足的神经系统疾病的发病机制。然而，这两种受体的直接相互作用仍然难以捉摸。在本研究中，我们首次证实了5-HT1AR和OX2R的异源二聚体形成。cAMP生物发光共振能量转移（BRET）生物传感器分析显示，与5-HT1AR组相比，转染这两种受体的HEK293T细胞中细胞cAMP的表达水平显著升高。此外，5-HT1AR和OX2R共转染的HEK293T细胞在激动剂处理后，细胞内钙水平显著上调。此外，western blotting数据显示，5-HT1AR和OX2R异源二聚体降低了细胞外信号调节激酶（ERK）和camp反应元件结合蛋白（CREB）的磷酸化水平。这些结果不仅揭示了5-HT1AR和OX2R异源二聚体的形成，而且表明异源二聚体影响下游信号通路，这将为研究这两种受体在大脑中的功能提供新的见解。
As G-protein-coupled receptors (GPCRs), 5-hydroxytryptamine 1A receptor (5-HT1AR) and orexin receptor 2 (OX2R) regulate the levels of the cellular downstream molecules. The heterodimers of different GPCRs play important roles in various of neurological diseases. Moreover, 5-HT1AR and OX2R are involved in the pathogenesis of neurological diseases such as depression with deficiency of hippocampus plasticity. However, the direct interaction of the two receptors remains elusive. In the present study, we firstly demonstrated the heterodimer formation of 5-HT1AR and OX2R. Exchange protein directly activated by cAMP (Epac) cAMP bioluminescence resonance energy transfer (BRET) biosensor analysis revealed that the expression levels of cellular cAMP significantly increased in HEK293T cells transfected with the two receptors compared with the 5-HT1AR group. Additionally, the cellular level of calcium was upregulated robustly in HEK293T cells co-transfected with 5-HT1AR and OX2R group after agonist treatment. Furthermore, western blotting data showed that 5-HT1AR and OX2R heterodimer decreased the levels of phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP-response element-binding protein (CREB). These results not only unraveled the formation of 5-HT1AR and OX2R heterodimer but also suggested that the heterodimer affected the downstream signaling pathway, which will provide new insights into the function of the two receptors in the brain.