Roles for Synapsins in Regulation of Synaptic Vesicle Traffic.

突触蛋白在突触小泡交通调节中的作用。

• 批准号: 11680751
• 负责人: HOSAKA Masahiro
• 金额: $ 2.18万
• 依托单位: Gunma University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11680751/
• 关键词: Synapsin; ATPase; Dimerization; Phosphorylation; Cyclosporine A; Sensory nerve ending; 神経; 小胞輸送

Homo- and heterodimerization of synapsins.Synapsins contain a central ATP-binding domain, the C-domain, that is highly homologous between synapsins and evolutionarily conserved in invertebrates. The crystal structure of the C-domain from synapsin I revealed that it constitutes a large (>300 amino acids), independently folded domain that forms a tight dimer with or without bound ATP.I have shown that the C-domains of all synapsins form homodimers, and that in addition, C-domains from different synapsins associate into heterodimers.A phospho-switch controls the dynamic association of synapsins with synaptic vesicles.Synapsins constitute a family of synaptic vesicle proteins essential for regulating neurotransmitter release. Only two domains are conserved in all synapsins : a short N-terminal A dontain with a single phosphorylation site for cAMP-dependent protein kinase (PKA) and CaM Kinase I, and a large central C domain that binds ATP and may be enzymatic. I have demonstrated that synap … More sin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles. Furthermore, we show that the A domain binds phospholipids and is inhibited by phosphorylation.Cyclosporine A-induced hypertension involves synapsin in renal sensory nerve endings.Synapsins are a family of synaptic vesicle phosphoproteins that are essential for normal regulation of neurotransmitter release at synapses. In addition to synaptic vesicles, synapsins are found on microvesicles in sensory nerve endings in peripheral tissues. However, the functions of the sensory microvesicles in general, and of synapsins in particular, are unknown. I have demonstrated in a mouse model that cyclosporine A (CsA) raises blood pressure by stimulating renal sensory nerve endings that contain synapsin-positive microvesicles. In knockout mice lacking synapsin I and II, sensory nerve endings are normally developed but not stimulated by CsA.The reflex activation of efferent sympathetic nerve activity and the increase in blood pressure by CsA seen in control are greatly attenuated in synapsin-deficient mice. These results provide a mechanistic explanation for CsA-induced acute hypertension and suggest that synapsins could serve as a drug target in this refractory condition. Furthermore, these data establish evidence that synapsin-containing sensory microvesicles perform an essential role in sensory transduction and suggest a role for synapsin phosphorylation in th is process. Less

突触的同源和异源二聚化。突触蛋白含有一个中心的atp结合结构域，即c结构域，它与突触蛋白高度同源，在无脊椎动物中具有进化保守性。突触蛋白1的c结构域的晶体结构表明，它构成了一个大的（bbb300个氨基酸），独立折叠的结构域，形成紧密的二聚体，有或没有结合ATP。我已经证明了所有突触的c结构域形成同型二聚体，另外，来自不同突触的c结构域结合成异型二聚体。磷酸化开关控制突触与突触囊泡的动态关联。突触蛋白是调节神经递质释放所必需的突触囊泡蛋白家族。所有突触中只有两个结构域是保守的：一个短的n端a结构域，具有camp依赖性蛋白激酶（PKA）和CaM激酶I的单一磷酸化位点，以及一个大的中央C结构域，结合ATP，可能是酶促的。我已经证明了突触，在所有突触共享的唯一磷酸化位点，A结构域更多的sin磷酸化，将突触从突触囊泡中分离出来。此外，我们发现A结构域结合磷脂并被磷酸化抑制。环孢素a诱导的高血压与肾感觉神经末梢突触有关。突触蛋白是一个突触囊泡磷酸化蛋白家族，对突触神经递质释放的正常调节至关重要。除了突触囊泡外，突触蛋白还存在于外周组织感觉神经末梢的微囊泡上。然而，感觉微泡的一般功能，特别是突触的功能，是未知的。我已经在小鼠模型中证明了环孢素a （CsA）通过刺激含有突触素阳性微泡的肾感觉神经末梢而升高血压。在缺乏突触素I和突触素II的敲除小鼠中，感觉神经末梢正常发育，但不受CsA刺激。在突触素缺乏小鼠中，传出交感神经活动的反射激活和CsA引起的血压升高在对照组中明显减弱。这些结果为csa诱导的急性高血压提供了机制解释，并提示突触素可能作为这种难治性疾病的药物靶点。此外，这些数据证明含有突触蛋白的感觉微泡在感觉转导中发挥重要作用，并提示突触蛋白磷酸化在这一过程中发挥作用。少

项目成果

Hosaka M,Hammer RE,Sudhof TC: "A phospho-switch controls the dynamic association of synapsins with synaptic vesicles."NEURON. 24. 377-387 (1999)

Hosaka M、Hammer RE、Sudhof TC：“磷酸开关控制突触蛋白与突触小泡的动态关联。”NEURON。

Zhang,W., Li,J.L., Hosaka.M., et al..: "Cyclosporine A-induced hypertension involves synapsin in renal sensory nerve endings."Proc.Natl.Acad.Sci.. 97. 9765-70 (2000)

张，W.，李，J.L.，Hosaka.M.，等：“环孢素 A 诱导的高血压涉及肾感觉神经末梢的突触蛋白。”Proc.Natl.Acad.Sci.. 97. 9765-70 (2000

Zhang W.,Li J.L.,Hosaka M., et al.: "Cyclosporine A-induced hypertension involves synapsin in renal sensory nerve endings."Proc.Natl.Acad.Sci.. 97. 9765-9770 (2000)

张 W.，Li J.L.，Hosaka M.，等：“环孢素 A 诱导的高血压涉及肾感觉神经末梢的突触蛋白。”Proc.Natl.Acad.Sci.. 97. 9765-9770 (2000)

Hosaka M, Sudhof TC.: "Homo-and heterodimerization of synapsins."J Biol Chem. 274. 16747-16753 (1999)

Hosaka M，Sudhof TC.：“突触蛋白的同二聚体和异二聚体。”J Biol Chem。

Hosaka M, Hammer RE, Sudhof TC.: "A phospho-switch controls the dynamic association of synapsins with synaptic vesicles"NEURON. 24. 377-87 (1999)

Hosaka M、Hammer RE、Sudhof TC.：“磷酸开关控制突触蛋白与突触小泡的动态关联”NEURON。