Roles for Synapsins in Regulation of Synaptic Vesicle Traffic.

突触素的同源和异源二聚化。突触素含有一个中心的ATP结合结构域，即C-结构域，该结构域在突触蛋白之间高度同源，在无脊椎动物中进化上保守。来自突触素I的C-结构域的晶体结构表明，它构成一个大的(&gt；300个氨基酸)独立折叠的结构域，形成一个紧密的二聚体，无论有没有结合的ATP。我已经证明，所有突触蛋白的C-结构域形成同源二聚体，此外，来自不同突触蛋白的C-结构域结合成异二聚体。一个磷酸开关控制突触蛋白与突触小泡的动态结合。突触蛋白组成一个突触小泡蛋白家族，对调节神经递质的释放至关重要。在所有突触素中，只有两个结构域是保守的：一个短的N-末端A，只有一个cAMP依赖的蛋白激酶(PKA)和CaM Kinase I的磷酸化位点，以及一个大的中央C结构域，它与ATP结合，可能是酶的。我已经演示了Synap…在所有突触蛋白共有的唯一磷酸化部位，A区有更多的SIN磷酸化，使突触蛋白从突触小泡中解离出来。此外，我们发现A结构域与磷脂结合并被磷酸化抑制。环孢素A诱导的高血压涉及肾感觉神经末梢的突触素。突触素是一个突触囊泡磷酸蛋白家族，对突触神经递质释放的正常调节至关重要。除了突触小泡外，在周围组织感觉神经末梢的微泡上也发现了突触蛋白。然而，一般情况下，感觉微囊的功能，特别是突触蛋白的功能，是未知的。我已经在小鼠模型中证明，环孢素A(CsA)通过刺激含有突触素阳性微囊的肾脏感觉神经末梢来提高血压。在缺乏突触素I和II的基因敲除小鼠中，感觉神经末梢正常发育，但不受CsA的刺激。在突触素缺乏的小鼠中，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小鼠中显著减弱。这些结果为CsA诱导的急性高血压提供了一种机制解释，并表明突触蛋白可能在这种难治性条件下作为药物靶点。此外，这些数据证实了含有突触素的感觉微泡在感觉转导中发挥着重要作用，并提示突触素的磷酸化在这一过程中起着重要作用。较少

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