脂筏对GABA_B受体的调控机制研究和GABA_B受体活性荧光探针开发
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摘要
脂筏作为细胞膜上信号传导的平台目前受到越来越多的关注,尤其是大量的研究已经显示脂筏对G蛋白偶联受体功能具有重要的调节作用。前期的研究已经发现与G蛋白偶联的GABA_B受体定位之脂筏结构中,所以探究脂筏对GABA_B受体的影响对揭示GABA_B受体的调控机制具有新的启示作用。
在本研究中,运用单点追踪技术追踪在异源HEK293细胞中实时追踪GABA_B受体在细胞膜上扩散运动,发现GABA_B受体的扩散特性主要由GABA_(B2)亚基决定。更进一步的,蔗糖密度梯度分析受体在脂筏中的定位显示GABA_(B2)亚基对受体扩散特性的决定作用取决于该亚基对受体在脂筏中定位的主导作用。因此,脂筏对限制GABA_B受体的侧向扩散具有关键的作用。
但是,GABA_B受体同脂筏的偶联并不是固定不变的。在HEK293细胞中,激动剂GABA能显著的提高GABA_B受体的扩散系数,这与采用甲基-β-环糊精(Methyl-β-cyclodextrin,MCD)破坏脂筏的效应相似。与受体扩散特性的变化相对应,共聚焦成像观测受体定位和蔗糖密度离心分析GABA_B的梯度分布显示,在异源细胞和神经元细胞中GABA_B受体激活之后在脂筏中的定位程度显著下降。所有结果共同说明激活GABA_B受体会诱导受体转移出脂筏区域。
随着GABA_B受体脂筏中定位程度的降低,受体所介导的G蛋白依赖的信号通路激活强度被削弱,例如下游G_(i/o)介导的ERK(Extracellular signal-regulated proteinkinases)磷酸化程度降低和G_(qi9)融合蛋白介导的IP_3(Inositol-1,4,5-trisphosphate)的产量减少,这些结果突显了脂筏正向促进GABA_B受体介导的G蛋白信号通路的重要作用。另外,脂筏还能协助调控参与GABA_B受体信号网络的信号分子的时空组织。信号分子随着活性的改变进入或者离开脂筏区域,从而决定了信号传递动态的启动和关闭。
我们的研究掀开了从脂筏的角度诠释GABA_B受体在细胞膜上动态行为和信号转导的新视野,GABA_B受体的这种定位特性非常值得重视。
为了在活细胞中直接观测GABA_B受体在细胞膜上的活性和功能并且直接在活细胞中标记GABA_B受体,基于GABA_B受体高亲和力的拮抗剂CGP64213的结构,本研究设计、合成并全面评价了一种活性导向的特异性标记细胞膜上GABA_B受体的小分子荧光探针即探针1。探针1由三个功能基团构成,即靶向定位基团、光亲和基团、荧光标记基团。探针可以用于光亲和性的标记在CHO细胞中瞬时表达的GABA_B受体。此外,探针能够特异性的识别GABA_(B1)亚基的配体结合口袋并表现出高效的光亲和性质,这使得探针对于在活细胞中研究GABA_B受体的定位和功能上具有重要应用价值。
Lipid raft domains have attracted much recent attention as platforms for plasma membrane signalling complexes. In particular, evidence is emerging that shows them to be key regulators of G protein coupled receptor function. Previous researches had shown that the G protein coupledγ-aminobutyric acid receptor B (GABA_B receptor) co-isolates with lipid raft domains from rat brain cerebellum, so exploring the effect that rafts play on GABA_B receptor may shed new light on understanding regulation mechanism of GABA_B receptor.
In the present study, single particle tracking approach was applied to follow surface diffusion of GABA_B receptors in real time when expressed ectopically in HEK293 cells. We found that the surface mobility of GABA_B receptors depends on the GABA_B: sunbunit. Furthermore, sucrose density gradients display that GABA_B receptors which diffused slowly presented in raft fractions, while GABA_(B1)-ASA which diffused freely did not localized in rafts selectively. Therefore, location in rafts is critical for restricting the lateral diffusion of GABA_B receptors.
However, the association between GABA_B receptors and rafts was not permanent. Treatment of tranfected HEK293 cells with agonist GABA significantly increased its diffusion coefficience, similar to the action of MCD (Methyl-β-cyclodextrin). In parallel with change on lateral mobility, confocal microscope imaging and sucrose density gradients both indicated the colocalization of GABA_B receptors with rafts decreased significantly upon activation in both heterogenous cells and neurons. Activation induced translocation of GABA_B receptor was convictively proved in this research.
The implication of the translocation of GABA_B receptors to nonraft domain is highlighted by attenuated G protein-dependent signaling, such as agonist-induced ERK phosphorylation and IP_3 acccumulation mediated by chimeric G_(qi9), with the decrease in location within rafts. Moreover, lipid rafts facilitated the spatial organization of signal compotents involved in GABA_B-mediated network by including or excluding them to variable extents, so that the transduction was switched on or off dynamicly.
Thus, a new perspective on surface behavior and signal transduction of GABA_B receptors modulated by rafts were proposed in the present study, so the intrinsic location property of the GABA_B receptors deserves more attentions on it.
In order to label the surface GABA_B receptors on living cells, a trimodular activity-based fluorescent probe was designed, synthesized and characterized based on the structure of CGP64213, an antagonist of GABA_B receptor. This probe can be applied to photoaffinity label the GABA_B receptor transiently expressed in CHO (Chinese hamster ovary) cells. Moreover, it exhibits specific binding activity at the ligand-binding pocket of GABA_(B1) subunits and high specificity of photoaffinity labeling, which makes the probe valuable for studying the localization and function of GABA_B receptors on living cells.
在本研究中,运用单点追踪技术追踪在异源HEK293细胞中实时追踪GABA_B受体在细胞膜上扩散运动,发现GABA_B受体的扩散特性主要由GABA_(B2)亚基决定。更进一步的,蔗糖密度梯度分析受体在脂筏中的定位显示GABA_(B2)亚基对受体扩散特性的决定作用取决于该亚基对受体在脂筏中定位的主导作用。因此,脂筏对限制GABA_B受体的侧向扩散具有关键的作用。
但是,GABA_B受体同脂筏的偶联并不是固定不变的。在HEK293细胞中,激动剂GABA能显著的提高GABA_B受体的扩散系数,这与采用甲基-β-环糊精(Methyl-β-cyclodextrin,MCD)破坏脂筏的效应相似。与受体扩散特性的变化相对应,共聚焦成像观测受体定位和蔗糖密度离心分析GABA_B的梯度分布显示,在异源细胞和神经元细胞中GABA_B受体激活之后在脂筏中的定位程度显著下降。所有结果共同说明激活GABA_B受体会诱导受体转移出脂筏区域。
随着GABA_B受体脂筏中定位程度的降低,受体所介导的G蛋白依赖的信号通路激活强度被削弱,例如下游G_(i/o)介导的ERK(Extracellular signal-regulated proteinkinases)磷酸化程度降低和G_(qi9)融合蛋白介导的IP_3(Inositol-1,4,5-trisphosphate)的产量减少,这些结果突显了脂筏正向促进GABA_B受体介导的G蛋白信号通路的重要作用。另外,脂筏还能协助调控参与GABA_B受体信号网络的信号分子的时空组织。信号分子随着活性的改变进入或者离开脂筏区域,从而决定了信号传递动态的启动和关闭。
我们的研究掀开了从脂筏的角度诠释GABA_B受体在细胞膜上动态行为和信号转导的新视野,GABA_B受体的这种定位特性非常值得重视。
为了在活细胞中直接观测GABA_B受体在细胞膜上的活性和功能并且直接在活细胞中标记GABA_B受体,基于GABA_B受体高亲和力的拮抗剂CGP64213的结构,本研究设计、合成并全面评价了一种活性导向的特异性标记细胞膜上GABA_B受体的小分子荧光探针即探针1。探针1由三个功能基团构成,即靶向定位基团、光亲和基团、荧光标记基团。探针可以用于光亲和性的标记在CHO细胞中瞬时表达的GABA_B受体。此外,探针能够特异性的识别GABA_(B1)亚基的配体结合口袋并表现出高效的光亲和性质,这使得探针对于在活细胞中研究GABA_B受体的定位和功能上具有重要应用价值。
Lipid raft domains have attracted much recent attention as platforms for plasma membrane signalling complexes. In particular, evidence is emerging that shows them to be key regulators of G protein coupled receptor function. Previous researches had shown that the G protein coupledγ-aminobutyric acid receptor B (GABA_B receptor) co-isolates with lipid raft domains from rat brain cerebellum, so exploring the effect that rafts play on GABA_B receptor may shed new light on understanding regulation mechanism of GABA_B receptor.
In the present study, single particle tracking approach was applied to follow surface diffusion of GABA_B receptors in real time when expressed ectopically in HEK293 cells. We found that the surface mobility of GABA_B receptors depends on the GABA_B: sunbunit. Furthermore, sucrose density gradients display that GABA_B receptors which diffused slowly presented in raft fractions, while GABA_(B1)-ASA which diffused freely did not localized in rafts selectively. Therefore, location in rafts is critical for restricting the lateral diffusion of GABA_B receptors.
However, the association between GABA_B receptors and rafts was not permanent. Treatment of tranfected HEK293 cells with agonist GABA significantly increased its diffusion coefficience, similar to the action of MCD (Methyl-β-cyclodextrin). In parallel with change on lateral mobility, confocal microscope imaging and sucrose density gradients both indicated the colocalization of GABA_B receptors with rafts decreased significantly upon activation in both heterogenous cells and neurons. Activation induced translocation of GABA_B receptor was convictively proved in this research.
The implication of the translocation of GABA_B receptors to nonraft domain is highlighted by attenuated G protein-dependent signaling, such as agonist-induced ERK phosphorylation and IP_3 acccumulation mediated by chimeric G_(qi9), with the decrease in location within rafts. Moreover, lipid rafts facilitated the spatial organization of signal compotents involved in GABA_B-mediated network by including or excluding them to variable extents, so that the transduction was switched on or off dynamicly.
Thus, a new perspective on surface behavior and signal transduction of GABA_B receptors modulated by rafts were proposed in the present study, so the intrinsic location property of the GABA_B receptors deserves more attentions on it.
In order to label the surface GABA_B receptors on living cells, a trimodular activity-based fluorescent probe was designed, synthesized and characterized based on the structure of CGP64213, an antagonist of GABA_B receptor. This probe can be applied to photoaffinity label the GABA_B receptor transiently expressed in CHO (Chinese hamster ovary) cells. Moreover, it exhibits specific binding activity at the ligand-binding pocket of GABA_(B1) subunits and high specificity of photoaffinity labeling, which makes the probe valuable for studying the localization and function of GABA_B receptors on living cells.
引文
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