Ubiquitination and inhibition of glycine receptor by HUWE1 in spinal cord dorsal horn
Ubiquitination and inhibition of glycine receptor by HUWE1 in spinal cord dorsal horn
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HUWE1对脊髓背角甘氨酸受体的泛素化和抑制
DOI：
10.1016/j.neuropharm.2019.02.002
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发表时间：
2019-04
影响因子：
4.7
通讯作者：
Hu Xiao-Dong
中科院分区：
文献类型：
--
作者：
Zhang Zi-Yang;Guo Zhen;LI Hu-Ling;He Yong-Tao;Duan Xing-Lian;Suo Zhan-Wei;Yang Xian;Hu Xiao-Dong
甘氨酸受体（GlyR）是由α（α1-α4）亚基和/或β亚基组成的五聚体蛋白。在成年动物的脊髓中，大多数抑制性甘氨酸能神经传递由含有α1亚基的GlyRs介导。减少甘氨酸能抑制（去抑制）被认为在病理性疼痛期间增加脊髓伤害性神经元的兴奋性和自发活动。然而，外周病变损害GlyRs-α1介导的突触抑制的分子机制仍不清楚。我们发现GlyRs-α1亚基的活性依赖性泛素化可能有助于外周炎症后甘氨酸能的去抑制。HUWE 1（HECT，乌巴，WWE domain containing 1）是一种E3泛素连接酶，定位于脊髓突触，与GlyRs-α1亚基特异性相互作用。HUWE 1通过泛素化GlyRs-α1，通过内吞途径降低GlyRs-α1的表面表达。在注射弗氏完全佐剂的小鼠的背角中，shRNA介导的HUWE 1敲低减弱了GlyRs-α1泛素化，增强了甘氨酸能突触传递并减轻了炎性疼痛。这些数据表明，GlyRs-α1的泛素修饰是外周炎症减少脊髓甘氨酸能抑制的重要途径，干扰HUWE 1活性通过恢复GlyRs-α1介导的突触传递产生镇痛作用。
Glycine receptors (GlyRs) are pentameric proteins that consist of α (α1-α4) subunits and/or β subunit. In the spinal cord of adult animals, the majority of inhibitory glycinergic neurotransmission is mediated by α1 subunit-containing GlyRs. The reduced glycinergic inhibition (disinhibition) is proposed to increase the excitabilities and spontaneous activities of spinal nociceptive neurons during pathological pain. However, the molecular mechanisms by which peripheral lesions impair GlyRs-α1-mediated synaptic inhibition remain largely unknown. Here we found that activity-dependent ubiquitination of GlyRs-α1 subunit might contribute to glycinergic disinhibition after peripheral inflammation. Our data showed that HUWE1 (HECT, UBA, WWE domain containing 1), an E3 ubiquitin ligase, located at spinal synapses and specifically interacted with GlyRs-α1 subunit. By ubiquitinating GlyRs-α1, HUWE1 reduced the surface expression of GlyRs-α1 through endocytic pathway. In the dorsal horn of Complete Freund's Adjuvant-injected mice, shRNA-mediated knockdown of HUWE1 blunted GlyRs-α1 ubiquitination, potentiated glycinergic synaptic transmission and attenuated inflammatory pain. These data implicated that ubiquitin modification of GlyRs-α1 represented an important way for peripheral inflammation to reduce spinal glycinergic inhibition and that interference with HUWE1 activity generated analgesic action by resuming GlyRs-α1-mediated synaptic transmission.
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影响因子：
64.5
作者：
Duan B;Cheng L;Bourane S;Britz O;Padilla C;Garcia-Campmany L;Krashes M;Knowlton W;Velasquez T;Ren X;Ross S;Lowell BB;Wang Y;Goulding M;Ma Q
通讯作者：
Ma Q
DOI：
--
发表时间：
--
期刊：
--
影响因子：
--
作者：
A. N. Acad;Sci;T. Takazawa;A. MacDermott
通讯作者：
A. N. Acad;Sci;T. Takazawa;A. MacDermott
影响因子：
16.2
作者：
Foster, Edmund;Wildner, Hendrik;Tudeau, Laetitia;Haueter, Sabine;Ralvenius, William T.;Jegen, Monika;Johannssen, Helge;Hoesli, Ladina;Haenraets, Karen;Ghanem, Alexander;Conzelmann, Karl-Klaus;Boesl, Michael;Zeilhofer, Hanns Ulrich
通讯作者：
Zeilhofer, Hanns Ulrich
DOI：
10.1523/jneurosci.3686-10.2010
发表时间：
2010-12-08
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Schwarz LA;Hall BJ;Patrick GN
通讯作者：
Patrick GN
影响因子：
16.2
作者：
Hayashi, Takashi;Thomas, Gareth M.;Huganir, Richard L.
通讯作者：
Huganir, Richard L.