每周论文更新----16 Sep 2016

zhouxuelong0258

每周论文更新----16 Sep 2016
周伯通博士

本周推送两篇文章，分别来自Nature Communications和Cell Reports杂志。文章的题目分别为：Cold sensitivity of TRPA1 is unveiled by the prolyl hydroxylation blockade-induced sensitization to ROS和 a2d-3 Is Required for Rapid Transsynaptic Homeostatic Signaling。

第一篇

Cold sensitivity of TRPA1 is unveiled by the prolyl hydroxylation blockade-induced sensitization to ROS

抑制脯氨酰羟化酶活性能够增强TRAP1对活性氧的致冷敏作用Miyake T, Nakamura S, Zhao M, So K, Inoue K, Numata T, Takahashi N, Shirakawa H, Mori Y, Nakagawa T, Kaneko S.

Nat Commun. 2016 Sep 15

PMID: 27628562

Abstract

Mammalian transient receptor potential ankyrin 1 (TRPA1) is a polymodal nociceptor that plays an important role in pain generation, but its role as a cold nociceptor is still controversial. Here, we propose that TRPA1 can sense noxious cold via transduction of reactive oxygen species (ROS) signalling. We show that inhibiting hydroxylation of a proline residue within the N-terminal ankyrin repeat of human TRPA1 by mutation or using aprolyl hydroxylase (PHD) inhibitor potentiates the cold sensitivity of TRPA1 in the presence of hydrogen peroxide. Inhibiting PHD in mice triggers mouse TRPA1 sensitization sufficiently to sense cold-evoked ROS, which causes cold hypersensitivity. Furthermore, this phenomenon underlies the acute cold hypersensitivity induced by the chemotherapeutic agent oxaliplatin or its metabolite oxalate. Thus, our findings provide evidence that blocking prolyl hydroxylation reveals TRPA1 sensitization to ROS, which enables TRPA1 to convert ROS signalling into cold sensitivity.

                               
登录/注册后可看大图

全文链接：http://www.nature.com/articles/ncomms12840

现在已知的比较确定的冷敏通道是TRPM8，而本文中的TRPA1通道由于是一种多模式的感受器，因此也可以感受冷觉。多模式感受器即是能感受多种刺激比如热、冷、化学性刺激的感受器。冷能够直接刺激TRPM8使其打开离子通道而感受冷觉，但是TRPA1如何感受冷觉并不是很清楚。之前的研究提示TRPA1感受冷刺激是通过线粒体产生的活性氧来介导的，但是活性氧如何介导TRPA1感受冷觉的机制仍然未知。本文作者发现，TRPA1的394位的脯氨酸的羟基化对于自由氧引起的冷觉感受起着重要作用。缺氧导致脯氨酰羟化酶（PHD）的活性降低，引起TRPA1 394位的脯氨酸羟基化程度增加，TRPA1对于自由氧的冷敏感性减弱；而使用PHD抑制剂抑制PHD活性，使TRPA1 394位的脯氨酸去羟基化，能够显著增强TRPA1对于自由氧的冷敏感性。因此，本文为TRPA1介导冷觉感受提供了重要的实验依据。

第二篇

a2δ-3 Is Required for Rapid Transsynaptic Homeostatic Signaling

a2δ-3对于跨突触自稳态的调控是必须的Wang T, Jones RT, Whippen JM, Davis GW.

Cell Rep. 2016 Sep 13

PMID:27626659

Abstract

The homeostatic modulation of neurotransmitter release, termed presynaptic homeostatic potentiation (PHP), is a fundamental type of neuromodulation, conserved from Drosophila to humans, that stabilizes information transfer at synaptic connections throughout the nervous system. Here, we demonstrate that α2δ-3, an auxiliary subunit of the presynaptic calcium channel, is required for PHP. The α2δ gene family has been linked to chronic pain, epilepsy, autism, and the action of two psychiatric drugs: gabapentin and pregabalin. We demonstrate that loss of α2δ-3 blocks both the rapid induction and sustained expression of PHP due to a failure to potentiate presynaptic calcium influx and the RIM-dependent readily releasable vesicle pool. These deficits are independent of α2δ-3-mediated regulation of baseline calcium influx and presynaptic action potential waveform. α2δ proteins reside at the extracellular face of presynaptic release sites throughout the nervous system, a site ideal for mediating rapid, transsynaptic homeostatic signaling in health and disease.

                               
登录/注册后可看大图

全文链接：http://www.cell.com/cell-reports/fulltext/S2211-1247(16)31094-4

突触之间的联系有一个很有意思的现象是自稳态的调控。当突触后膜上的神经递质受体由于某种原因被部分阻断或者抑制以后，突触前膜的神经递质会代偿性的释放增加，从而导致基本的突触联系不受影响，这种现象就叫突触的自稳态调控。本文阐述了一种突触前膜自稳态调控的机制即突触前膜钙离子通道的辅助亚基α2δ-3对于突触前膜自稳态调控起着重要的作用。α2δ-3辅助亚基通过增加突触前膜的钙离子内流进而导致突触前膜神经递质囊泡的释放增加实现自稳态调控。因此，α2δ-3辅助亚基的功能失调可能是某些疾病产生的可能机制，有待后续研究。

这里是服务疼痛基础研究科研人员的微信号“疼痛研究论坛”。我们：

• 关注疼痛基础研究进展
• 推荐高水平前沿研究
• 为疼痛基础研究人员提供交流平台
  
  

欢迎长按二维码关注。

                               
登录/注册后可看大图