Partial regulation of serotonin transporter function by gamma-synuclein.
Partial regulation of serotonin transporter function by gamma-synuclein.
复制标题
γ-突触核蛋白对血清素转运蛋白功能的部分调节。
DOI：
10.1016/j.neulet.2009.02.033
复制
发表时间：
2009
影响因子：
2.5
通讯作者：
Sidhu,Anita
中科院分区：
文献类型：
--
作者：
Wersinger,Christophe;Sidhu,Anita
人α-突触核蛋白（α-Syn）通过其运输和调节细胞表面表达，从而调节多巴胺、5-羟色胺和去甲肾上腺素转运体的活性，在维持脑内单胺神经递质的稳态中起作用。在这里，我们研究了突触核蛋白家族的其他成员，γ-突触核蛋白（γ-Syn）和β-突触核蛋白（β-Syn）是否可以类似地调节5-羟色胺转运蛋白（SERT）。在用SERT和γ-Syn共转染的Ltk−细胞中，γ-Syn以依赖于其表达水平的方式减少[3 H]5-HT摄取。与仅表达SERT的细胞相比，SERT活性的降低是通过降低转运蛋白的Vmax而实现的，而Km没有变化。相比之下，β-Syn共表达未能改变SERT摄取活性，并且在β-Syn存在下，Vmax和Km均未改变。γ-Syn对SERT的调节仅是部分的，即使在γ-Syn的高表达水平下也观察到SERT活性的最大降低约27%。相比之下，α-Syn在与γ-Syn相同的表达水平下使SERT活性减弱约65%。免疫共沉淀研究表明，γ-Syn或α-Syn与SERT之间存在异聚体蛋白质：蛋白质复合物，而β-Syn未能与SERT发生物理相互作用。α-Syn和γ-Syn与SERT共定位于大鼠原代Raphae核神经元。这些研究证明了γ-Syn在调节5-HT突触可用性和稳态中的新生理作用，并且可能与SERT功能失调的抑郁症和心境障碍相关。
Human α-synuclein (α-Syn) is instrumental in maintaining homeostasis of monoamine neurotransmitters in brain, through its trafficking, and regulation of the cell surface expression and, thereby, activity of dopamine, serotonin and norepinephrine transporters. Here we have investigated whether other members of the synuclein family of proteins, γ-synuclein (γ-Syn) and β-synuclein (β-Syn) can similarly modulate the serotonin transporter (SERT). In Ltk−cells co-transfected with SERT and γ-Syn, γ-Syn reduced [3H]5-HT uptake, in a manner dependent on its expression levels. The decrease in SERT activity was via decreased Vmaxof the transporter, without change in Km, compared to cells expressing only SERT. By contrast, β-Syn co-expression failed to alter SERT uptake activity, and neither the Vmaxnor the Kmwas changed in the presence of β-Syn. γ-Syn modulation of SERT was only partial, with a maximal ∼27% decrease in SERT activity seen even at high expression levels of γ-Syn. By contrast, α-Syn attenuated SERT activity by ∼65% at identical expression levels as γ-Syn. Co-immunoprecipitation studies showed the presence of heteromeric protein:protein complexes between γ-Syn or α-Syn and SERT, while β-Syn failed to physically interact with SERT. Both α-Syn and γ-Syn colocalized with SERT in rat primary raphae nuclei neurons. These studies document a novel physiological role for γ-Syn in regulating 5-HT synaptic availability and homeostasis, and may be of relevance in depression and mood disorders, where SERT function is dysregulated.