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A lower X-gate in TASK channels traps inhibitors within the vestibule 期刊论文
NATURE, 2020
作者:  Chen, Tao;  Nomura, Kinya;  Wang, Xiaolin;  Sohrabi, Reza;  Xu, Jin;  Yao, Lingya;  Paasch, Bradley C.;  Ma, Li;  Kremer, James;  Cheng, Yuti;  Zhang, Li;  Wang, Nian;  Wang, Ertao;  Xin, Xiu-Fang;  He, Sheng Yang
收藏  |  浏览/下载:32/0  |  提交时间:2020/07/03

TWIK-related acid-sensitive potassium (TASK) channels-members of the two pore domain potassium (K-2P) channel family-are found in neurons(1), cardiomyocytes(2-4) and vascular smooth muscle cells(5), where they are involved in the regulation of heart rate(6), pulmonary artery tone(5,7), sleep/wake cycles(8) and responses to volatile anaesthetics(8-11). K-2P channels regulate the resting membrane potential, providing background K+ currents controlled by numerous physiological stimuli(12-15). Unlike other K-2P channels, TASK channels are able to bind inhibitors with high affinity, exceptional selectivity and very slow compound washout rates. As such, these channels are attractive drug targets, and TASK-1 inhibitors are currently in clinical trials for obstructive sleep apnoea and atrial fibrillation(16). In general, potassium channels have an intramembrane vestibule with a selectivity filter situated above and a gate with four parallel helices located below  however, the K-2P channels studied so far all lack a lower gate. Here we present the X-ray crystal structure of TASK-1, and show that it contains a lower gate-which we designate as an '  X-gate'  -created by interaction of the two crossed C-terminal M4 transmembrane helices at the vestibule entrance. This structure is formed by six residues ((VLRFMT248)-V-243) that are essential for responses to volatile anaesthetics(10), neurotransmitters(13) and G-protein-coupled receptors(13). Mutations within the X-gate and the surrounding regions markedly affect both the channel-open probability and the activation of the channel by anaesthetics. Structures of TASK-1 bound to two high-affinity inhibitors show that both compounds bind below the selectivity filter and are trapped in the vestibule by the X-gate, which explains their exceptionally low washout rates. The presence of the X-gate in TASK channels explains many aspects of their physiological and pharmacological behaviour, which will be beneficial for the future development and optimization of TASK modulators for the treatment of heart, lung and sleep disorders.


The X-ray crystal structure of the potassium channel TASK-1 reveals the presence of an X-gate, which traps small-molecule inhibitors in the intramembrane vestibule and explains their low washout rates from the channel.


  
Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells 期刊论文
NATURE, 2020, 577 (7792) : 676-+
作者:  Zhao, Ruozhu;  Chen, Xin;  Ma, Weiwei;  Zhang, Jinyu;  Guo, Jie;  Zhong, Xiu;  Yao, Jiacheng;  Sun, Jiahui;  Rubinfien, Julian;  Zhou, Xuyu;  Wang, Jianbin;  Qi, Hai
收藏  |  浏览/下载:12/0  |  提交时间:2020/07/03

Empirical and anecdotal evidence has associated stress with accelerated hair greying (formation of unpigmented hairs)(1,2), but so far there has been little scientific validation of this link. Here we report that, in mice, acute stress leads to hair greying through the fast depletion of melanocyte stem cells. Using a combination of adrenalectomy, denervation, chemogenetics(3,4), cell ablation and knockout of the adrenergic receptor specifically in melanocyte stem cells, we find that the stress-induced loss of melanocyte stem cells is independent of immune attack or adrenal stress hormones. Instead, hair greying results from activation of the sympathetic nerves that innervate the melanocyte stem-cell niche. Under conditions of stress, the activation of these sympathetic nerves leads to burst release of the neurotransmitter noradrenaline (also known as norepinephrine). This causes quiescent melanocyte stem cells to proliferate rapidly, and is followed by their differentiation, migration and permanent depletion from the niche. Transient suppression of the proliferation of melanocyte stem cells prevents stress-induced hair greying. Our study demonstrates that neuronal activity that is induced by acute stress can drive a rapid and permanent loss of somatic stem cells, and illustrates an example in which the maintenance of somatic stem cells is directly influenced by the overall physiological state of the organism.


Stress induces hair greying in mice through depletion of melanocyte stem cells, which is mediated by the activation of sympathetic nerves rather than through immune attack or adrenal stress hormones.


  
The environmental and socioeconomic trade-offs of importing crops to meet domestic food demand in China 期刊论文
ENVIRONMENTAL RESEARCH LETTERS, 2019, 14 (9)
作者:  Huang, Guorui;  Yao, Guolin;  Zhao, Jing;  Lisk, Matthew D.;  Yu, Chaoqing;  Zhang, Xin
收藏  |  浏览/下载:7/0  |  提交时间:2019/11/27
crop trade  sustainability  nitrogen pollution  crop portfolio optimization  
How does the implementation of the Policy of Electricity Substitution influence green economic growth in China? 期刊论文
ENERGY POLICY, 2019, 131: 251-261
作者:  Wu, Wanlu;  Cheng, Yuanyuan;  Lin, Xiqiao;  Yao, Xin
收藏  |  浏览/下载:7/0  |  提交时间:2019/11/27
Green economic growth  Electricity substitution policy  Input-output (IO)  
Greening in Rural Areas Increases the Surface Urban Heat Island Intensity 期刊论文
GEOPHYSICAL RESEARCH LETTERS, 2019, 46 (4) : 2204-2212
作者:  Yao, Rui;  Wang, Lunche;  Huang, Xin;  Gong, Wei;  Xia, Xiangao
收藏  |  浏览/下载:6/0  |  提交时间:2019/04/09
Flexible decapyrrylcorannulene hosts 期刊论文
NATURE COMMUNICATIONS, 2019, 10
作者:  Xu, Yun-Yan;  Tian, Han-Rui;  Li, Shu-Hui;  Chen, Zuo-Chang;  Yao, Yang-Rong;  Wang, Shan-Shan;  Zhang, Xin;  Zhu, Zheng-Zhong;  Deng, Shun-Liu;  Zhang, Qianyan;  Yang, Shangfeng;  Xie, Su-Yuan;  Huang, Rong-Bin;  Zheng, Lan-Sun
收藏  |  浏览/下载:9/0  |  提交时间:2019/11/27
Evolution of the Subauroral Polarization Stream Oscillation During the Severe Geomagnetic Storm on 20 November 2003 期刊论文
GEOPHYSICAL RESEARCH LETTERS, 2019, 46 (2) : 599-607
作者:  He, Fei;  Zhang, Xiao-Xin;  Wang, Wenbin;  Pu, Zu-Yin;  Zong, Qiu-Gang;  Yao, Zhonghua;  Wei, Yong;  Ren, Zhi-Peng;  Yue, Xinan;  Liu, Libo;  Wan, Weixing
收藏  |  浏览/下载:13/0  |  提交时间:2019/04/09
The role of alternative polyadenylation in the antiviral innate immune response 期刊论文
NATURE COMMUNICATIONS, 2017, 8
作者:  Jia, Xin;  Yuan, Shaochun;  Wang, Yao;  Fu, Yonggui;  Ge, Yong;  Ge, Yutong;  Lan, Xihong;  Feng, Yuchao;  Qiu, Feifei;  Li, Peiyi;  Chen, Shangwu;  Xu, Anlong
收藏  |  浏览/下载:7/0  |  提交时间:2019/11/27
Single-cell RNA sequencing unveils an IL-10-producing helper subset that sustains humoral immunity during persistent infection 期刊论文
NATURE COMMUNICATIONS, 2018, 9
作者:  Xin, Gang;  Zander, Ryan;  Schauder, David M.;  Chen, Yao;  Weinstein, Jason S.;  Drobyski, William R.;  Tarakanova, Vera;  Craft, Joseph;  Cui, Weiguo
收藏  |  浏览/下载:5/0  |  提交时间:2019/11/27
The paraventricular thalamus is a critical thalamic area for wakefulness 期刊论文
SCIENCE, 2018, 362 (6413) : 429-+
作者:  Ren, Shuancheng;  Wang, Yaling;  Yue, Faguo;  Cheng, Xiaofang;  Dang, Ruozhi;  Qiao, Qicheng;  Sun, Xueqi;  Li, Xin;  Jiang, Qian;  Yao, Jiwei;  Qin, Han;  Wang, Guanzhong;  Liao, Xiang;  Gao, Dong;  Xia, Jianxia;  Zhang, Jun;  Hu, Bo;  Yan, Junan;  Wang, Yanjiang;  Xu, Min;  Han, Yunyun;  Tang, Xiangdong;  Chen, Xiaowei;  He, Chao;  Hu, Zhian
收藏  |  浏览/下载:9/0  |  提交时间:2019/11/27