Nature：新研究发现一蛋白质控制神经递质

近日，Nature上的一项新研究发现一蛋白质能控制神经递质，研究结果可能有助于设计开发新的药物，以改善脑细胞之间的沟通、有效治疗神经系统疾病。

近日，威尔康乃尔医学院的科学家发现，单蛋白质--alpha 2 delta具有控制神经递质和其他突触大脑神经元之间交流的化学物质的体积流量。这项研究发表在Nature杂志上，研究揭示了脑细胞如何通过这些信号彼此交流、传达思想、感情和行动，其中alpha 2 delta起到了至关重要的作用。

在这项研究中，研究人员还提示了止痛药Lyrica是如何发挥作用，alpha 2 delta是这种药物的靶标。

研究人员发现，alpha 2 delta决定了多少钙离子通道神经元之间的突触。触发进入这些渠道中的钙进入突触的化学信号传输，所以传输体积和神经传导速度取决于这些通道的可用性。

研究人员发现，去除alpha 2 delta抑制了脑细胞突触通过钙离子通道获得钙。 但是，如果你过度alpha 2 delta的话，突触间通道数增了加两倍的。

在此之前的研究，Lyrica结合alpha 2 delta是神经性疼痛、癫痫和纤维肌痛的有效药物，但很少有人理解这种蛋白质工程是如何控制突触的。

doi:10.1038/nature11033
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α2δ expression sets presynaptic calcium channel abundance and release probability

Michael B. Hoppa,Beatrice Lana,Wojciech Margas,Annette C. Dolphin& Timothy A. Ryan

Synaptic neurotransmitter release is driven by Ca²⁺ influx through active zone voltage-gated calcium channels (VGCCs)^{1, 2}. Control of active zone VGCC abundance and function remains poorly understood. Here we show that a trafficking step probably sets synaptic VGCC levels in rats, because overexpression of the pore-forming α1_A VGCC subunit fails to change synaptic VGCC abundance or function. α2δs are a family of glycosylphosphatidylinositol (GPI)-anchored VGCC-associated subunits³ that, in addition to being the target of the potent neuropathic analgesics gabapentin and pregabalin (α2δ-1 and α2δ-2)^{4, 5}, were also identified in a forward genetic screen for pain genes (α2δ-3)⁶. We show that these proteins confer powerful modulation of presynaptic function through two distinct molecular mechanisms. First, α2δ subunits set synaptic VGCC abundance, as predicted from their chaperone-like function when expressed in non-neuronal cells^{3, 7}. Second, α2δs configure synaptic VGCCs to drive exocytosis through an extracellular metal ion-dependent adhesion site (MIDAS), a conserved set of amino acids within the predicted von Willebrand A domain of α2δ. Expression of α2δ with an intact MIDAS motif leads to an 80% increase in release probability, while simultaneously protecting exocytosis from blockade by an intracellular Ca²⁺ chelator. α2δs harbouring MIDAS site mutations still drive synaptic accumulation of VGCCs; however, they no longer change release probability or sensitivity to intracellular Ca²⁺ chelators. Our data reveal dual functionality of these clinically important VGCC subunits, allowing synapses to make more efficient use of Ca²⁺ entry to drive neurotransmitter release.