GABA_B受体神经保护功能的分子机制研究及其与G蛋白动态相互作用研究
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摘要
GABAB受体是中枢神经系统中主要的抑制性神经递质γ-氨基丁酸(GABA)的代谢型受体,在神经元的突触前和突触后都有广泛的表达。同时,它也是GPCR C家族成员之一,与Gi/o型G蛋白相互偶联,介导缓慢而持久的神经突触活动。GABAB受体功能的减弱或亢进会导致多种中枢神经系统疾病,如癫痫,痉挛,焦虑,抑郁,疼痛,药物成瘾,认知损伤等,是重要的药物靶点。
最近的研究表明,GABAB受体的激活具有神经保护的功能,但是,其作用的具体分子机制还并不清楚。在本课题研究的第一部分,我们以低钾诱导的小脑颗粒神经元的凋亡作为细胞模型,确认了GABAB受体的神经保护作用。进一步,我们发现GABAB受体的激活介导了PI3K/Akt信号通路,并且这条信号通路在GABAB受体介导的神经保护作用中起到了重要的作用。进而,我们有意思的发现GABAB受体的激活可以引起IGF-1受体活性的增强。用IGF-1受体的抑制剂抑制受体活性或用RNA干扰降低IGF-1受体表达后,GABAB受体介导的Akt的激活被抑制了。这表明GABAB受体可以转激活IGF-1受体并进一步激活了Akt信号通路。同时,通过免疫共沉淀和配体竞争实验,我们发现GABAB受体可以与IGF-1受体相互作用并且.两者之间的转激活效应是配体非依赖的。这个研究一方面阐明了GABAB受体神经保护功能的分子机制,暗示GABAB受体在神经退行性疾病中潜在药理学功能；另一方面,这首次发现了GABAB受体对RTK的转激活作用,也进一步表明了GPCR与RTK之间信号交联的重要意义。
新的蛋白质与蛋白质相互作用研究手段的建立使得传统的GPCR与G蛋白相互作用的基于“碰撞”的模型受到了挑战。在GPCR A家族成员的研究表明受体与G蛋白之间可以形成稳定的复合物,并且受体的激活并不导致G蛋白三聚体的解离。但是,对GPCR C家族成员与G蛋白的相互作用的研究还没有报道。在第二部分的研究中,我们用BRET和TR-FRET的方法研究了GABAb受体与G蛋白的相互作用,以及受体激活前后受体与G蛋白,G蛋白Gα和Gβγ亚基之间相互作用的动态变化。我们的结果暗示G蛋白可以和GABAB受体预结合,并且受体激活后会使得G蛋白与GABAB受体相互作用的减弱,同时也导致了Gα和Gβγ之间相互作用的变化。这些结果一方面证实了G蛋白可以受体预结合并伴随着受体的激活呈现动态的变化,另一方面也为建立基于BRET技术的GABAB受体的新的药物筛选细胞模型提供思路。
GABAB receptor is the metabotropic recetor of y-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the central nevous system (CNS). It is widely expressed presynaptically and postsynaptically. Meanwhile, GABAB receptor belongs to G protein coupled receptor family (GPCR) group C and couples with Gi/o protein, mediating slow and prelonged synaptic activity. Hypoactivity or hyperactivity of GABAB receptor would reslut in various nevous system disorders, such as epilepsy, spasticity, anxiety, stress, depression, addiction, pains and memory dysfunction. Therefore, it is an important drug target.
The activation of GABAB receptor is reported to promote neuronal survival under ischemia and metabolic stress. However, the molecular mechanism by which the GABAB receptor mediates neuroprotection remains to be elucidated. In the first study of our work, we confirmed that the activation of GABAB receptor protected cerebellar granule cells (CGNs) from potassium-induced apoptosis. Furthermore, we found that the actvation of GABAB receptor increased P13K/Akt signal pathway activity and this pathway played an important role in the antiapoptosis function of GABAB receptor. Interestingly, we found the GABAB receptor activation increased insulin-like growth factor 1 receptor (IGF-1R) phosphorylation. When we used the inhibitor of IGF-1R to treat the neurons or knockdowned the expression of IGF-1R in both CGNs and transfected MEF cells, the agonist of GABAB receptor, baclofen-stimulated Akt phosphorylation was reduced significantly, which suggested the activation of GABAB receptor transactivated IGF-1R and then induced Akt pathway. Meanwhile, using co-immunoprecipitation and ligand competition assay, we showed that there was an interaction between GABAB receptor and IGF-1R while the transactivation of IGF-1R by GABAB receptor was ligand-independent. These results showed a new function for GABAB receptor and further highlighted the importance of functional cross-talk networks between GPCRs and receptor tyrosine kinases (RTKs). Meanwhile, our results revealed GABAB receptor as a potential drug target for the treatment of neurodegenerative disorders.
The new approaches for protein-protein interaction brought challenge to traditional GPCR-G protein collision-interaction model. The research on GPCR group A members found that the receptor and G protein could form stable complex and G protein wouldn't disassociate during the receptor activation. However, there is no result about GPCR group C members. In the secondary part of our work, we used BRET and TR-FRET to study the dynamic change between GABAB receptor and G protein. We showed that G protein pre-coupled with GABAB receptor and both the interaction between GABAB receptor and G protein and Gαand Gβγwere decreased. These results might provide a new insight for drug screening cell model of GABAB receptor.
最近的研究表明,GABAB受体的激活具有神经保护的功能,但是,其作用的具体分子机制还并不清楚。在本课题研究的第一部分,我们以低钾诱导的小脑颗粒神经元的凋亡作为细胞模型,确认了GABAB受体的神经保护作用。进一步,我们发现GABAB受体的激活介导了PI3K/Akt信号通路,并且这条信号通路在GABAB受体介导的神经保护作用中起到了重要的作用。进而,我们有意思的发现GABAB受体的激活可以引起IGF-1受体活性的增强。用IGF-1受体的抑制剂抑制受体活性或用RNA干扰降低IGF-1受体表达后,GABAB受体介导的Akt的激活被抑制了。这表明GABAB受体可以转激活IGF-1受体并进一步激活了Akt信号通路。同时,通过免疫共沉淀和配体竞争实验,我们发现GABAB受体可以与IGF-1受体相互作用并且.两者之间的转激活效应是配体非依赖的。这个研究一方面阐明了GABAB受体神经保护功能的分子机制,暗示GABAB受体在神经退行性疾病中潜在药理学功能；另一方面,这首次发现了GABAB受体对RTK的转激活作用,也进一步表明了GPCR与RTK之间信号交联的重要意义。
新的蛋白质与蛋白质相互作用研究手段的建立使得传统的GPCR与G蛋白相互作用的基于“碰撞”的模型受到了挑战。在GPCR A家族成员的研究表明受体与G蛋白之间可以形成稳定的复合物,并且受体的激活并不导致G蛋白三聚体的解离。但是,对GPCR C家族成员与G蛋白的相互作用的研究还没有报道。在第二部分的研究中,我们用BRET和TR-FRET的方法研究了GABAb受体与G蛋白的相互作用,以及受体激活前后受体与G蛋白,G蛋白Gα和Gβγ亚基之间相互作用的动态变化。我们的结果暗示G蛋白可以和GABAB受体预结合,并且受体激活后会使得G蛋白与GABAB受体相互作用的减弱,同时也导致了Gα和Gβγ之间相互作用的变化。这些结果一方面证实了G蛋白可以受体预结合并伴随着受体的激活呈现动态的变化,另一方面也为建立基于BRET技术的GABAB受体的新的药物筛选细胞模型提供思路。
GABAB receptor is the metabotropic recetor of y-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the central nevous system (CNS). It is widely expressed presynaptically and postsynaptically. Meanwhile, GABAB receptor belongs to G protein coupled receptor family (GPCR) group C and couples with Gi/o protein, mediating slow and prelonged synaptic activity. Hypoactivity or hyperactivity of GABAB receptor would reslut in various nevous system disorders, such as epilepsy, spasticity, anxiety, stress, depression, addiction, pains and memory dysfunction. Therefore, it is an important drug target.
The activation of GABAB receptor is reported to promote neuronal survival under ischemia and metabolic stress. However, the molecular mechanism by which the GABAB receptor mediates neuroprotection remains to be elucidated. In the first study of our work, we confirmed that the activation of GABAB receptor protected cerebellar granule cells (CGNs) from potassium-induced apoptosis. Furthermore, we found that the actvation of GABAB receptor increased P13K/Akt signal pathway activity and this pathway played an important role in the antiapoptosis function of GABAB receptor. Interestingly, we found the GABAB receptor activation increased insulin-like growth factor 1 receptor (IGF-1R) phosphorylation. When we used the inhibitor of IGF-1R to treat the neurons or knockdowned the expression of IGF-1R in both CGNs and transfected MEF cells, the agonist of GABAB receptor, baclofen-stimulated Akt phosphorylation was reduced significantly, which suggested the activation of GABAB receptor transactivated IGF-1R and then induced Akt pathway. Meanwhile, using co-immunoprecipitation and ligand competition assay, we showed that there was an interaction between GABAB receptor and IGF-1R while the transactivation of IGF-1R by GABAB receptor was ligand-independent. These results showed a new function for GABAB receptor and further highlighted the importance of functional cross-talk networks between GPCRs and receptor tyrosine kinases (RTKs). Meanwhile, our results revealed GABAB receptor as a potential drug target for the treatment of neurodegenerative disorders.
The new approaches for protein-protein interaction brought challenge to traditional GPCR-G protein collision-interaction model. The research on GPCR group A members found that the receptor and G protein could form stable complex and G protein wouldn't disassociate during the receptor activation. However, there is no result about GPCR group C members. In the secondary part of our work, we used BRET and TR-FRET to study the dynamic change between GABAB receptor and G protein. We showed that G protein pre-coupled with GABAB receptor and both the interaction between GABAB receptor and G protein and Gαand Gβγwere decreased. These results might provide a new insight for drug screening cell model of GABAB receptor.
引文
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