近日,，Nature上的一項新研究發(fā)現(xiàn)一蛋白質(zhì)能控制神經(jīng)遞質(zhì)，研究結(jié)果可能有助于設(shè)計開發(fā)新的藥物,，以改善腦細(xì)胞之間的溝通,、有效治療神經(jīng)系統(tǒng)疾病。
近日,，威爾康乃爾醫(yī)學(xué)院的科學(xué)家發(fā)現(xiàn),，單蛋白質(zhì)--alpha 2 delta具有控制神經(jīng)遞質(zhì)和其他突觸大腦神經(jīng)元之間交流的化學(xué)物質(zhì)的體積流量。這項研究發(fā)表在Nature雜志上,，研究揭示了腦細(xì)胞如何通過這些信號彼此交流,、傳達(dá)思想、感情和行動,，其中alpha 2 delta起到了至關(guān)重要的作用,。
在這項研究中,，研究人員還提示了止痛藥Lyrica是如何發(fā)揮作用，alpha 2 delta是這種藥物的靶標(biāo),。
研究人員發(fā)現(xiàn),，alpha 2 delta決定了多少鈣離子通道神經(jīng)元之間的突觸。觸發(fā)進(jìn)入這些渠道中的鈣進(jìn)入突觸的化學(xué)信號傳輸,，所以傳輸體積和神經(jīng)傳導(dǎo)速度取決于這些通道的可用性,。
研究人員發(fā)現(xiàn)，去除alpha 2 delta抑制了腦細(xì)胞突觸通過鈣離子通道獲得鈣,。 但是,，如果你過度alpha 2 delta的話，突觸間通道數(shù)增了加兩倍的,。
在此之前的研究,，Lyrica結(jié)合alpha 2 delta是神經(jīng)性疼痛、癲癇和纖維肌痛的有效藥物,，但很少有人理解這種蛋白質(zhì)工程是如何控制突觸的,。（生物谷：Bioon.com）
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 α1A 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 cells3, 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.
