A heteromeric Texas coral snake toxin targets acid-sensing ion channels to produce pain.
A heteromeric Texas coral snake toxin targets acid-sensing ion channels to produce pain.
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DOI：
10.1038/nature10607
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发表时间：
2011-11-16
期刊：
影响因子：
64.8
通讯作者：
Julius, David
中科院分区：
文献类型：
--
作者：
Bohlen, Christopher J.;Chesler, Alexander T.;Sharif-Naeini, Reza;Medzihradszky, Katalin F.;Zhou, Sharleen;King, David;Sanchez, Elda E.;Burlingame, Alma L.;Basbaum, Allan I.;Julius, David
引起不适或疼痛的天然产品代表了探测痛觉潜在分子机制的宝贵工具。植物来源的刺激物在这方面占主导地位，但动物毒液也进化到通过靶向神经元和受体来避免捕食者，这些神经元和受体的激活产生有害的感觉。因此，毒液提供了丰富多样的小分子和蛋白质药效团来源，可用于表征和操纵疼痛信号传导途径的关键组分。考虑到这一点，我们进行了一个公正的体外筛选，以确定蛇毒能够激活体感神经元。得克萨斯州的珊瑚蛇（Micrurus tener tener）的毒液会产生强烈而持续的疼痛，它会刺激一大群感觉神经元。纯化的活性物质（MitTx）由Kunitz-和磷脂酶A2-样蛋白之间的异聚复合物组成，所述异聚复合物一起作为酸敏感离子通道（ASIC）的有效、持久和选择性激动剂起作用，当与酸性pH相比时显示出相等或更大的功效。在更酸性的条件下（pH < 6.5），MitTx极大地增强（>100倍）质子诱发的ASIC 2a通道活化。这些观察结果提出了ASIC通道作为细胞外质子和其他尚未鉴定的内源性因子的符合检测器的可能性。纯化的MitTx通过激活辣椒素敏感神经纤维上的ASIC 1通道在小鼠中激发强烈的疼痛相关行为。这些发现揭示了蛇毒产生疼痛的机制，并突出了ASIC 1通道对伤害性感受的意外贡献。
Natural products that elicit discomfort or pain represent invaluable tools for probing molecular mechanisms underlying pain sensation. Plant-derived irritants have predominated in this regard, but animal venoms have also evolved to avert predators by targeting neurons and receptors whose activation produces noxious sensations. As such, venoms provide a rich and varied source of small molecule and protein pharmacophores that can be exploited to characterize and manipulate key components of the pain-signaling pathway. With this in mind, we carried out an unbiased in vitro screen to identify snake venoms capable of activating somatosensory neurons. Venom from the Texas coral snake (Micrurus tener tener), whose bite produces intense and unremitting pain, excited a large cohort of sensory neurons. The purified active species (MitTx) consists of a heteromeric complex between Kunitz- and phospholipase A2-like proteins that together function as a potent, persistent, and selective agonist for acid-sensing ion channels (ASICs), showing equal or greater efficacy when compared with acidic pH. MitTx is highly selective for the ASIC1 subtype at neutral pH; under more acidic conditions (pH < 6.5), MitTx massively potentiates (>100-fold) proton-evoked activation of ASIC2a channels. These observations raise the possibility that ASIC channels function as coincidence detectors for extracellular protons and other, as yet unidentified, endogenous factors. Purified MitTx elicits robust pain-related behavior in mice via activation of ASIC1 channels on capsaicin-sensitive nerve fibers. These findings reveal a mechanism whereby snake venoms produce pain, and highlight an unexpected contribution of ASIC1 channels to nociception.
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影响因子：
2.9
作者：
Jacobson, MP;Pincus, DL;Friesner, RA
通讯作者：
Friesner, RA
影响因子：
16.2
作者：
Askwith, CC;Cheng, C;Welsh, MJ
通讯作者：
Welsh, MJ
影响因子：
64.5
作者：
Ziemann AE;Allen JE;Dahdaleh NS;Drebot II;Coryell MW;Wunsch AM;Lynch CM;Faraci FM;Howard MA 3rd;Welsh MJ;Wemmie JA
通讯作者：
Wemmie JA
DOI：
10.1073/pnas.011404498
发表时间：
2001-01-16
影响因子：
11.1
作者：
Sutherland, SP;Benson, CJ;McCleskey, EW
通讯作者：
McCleskey, EW
影响因子：
4.8
作者：
Waldmann, R;Bassilana, F;Lazdunski, M
通讯作者：
Lazdunski, M