Orai1 is a crucial downstream partner of group I metabotropic glutamate receptor signaling in dorsal horn neurons.
Orai1 is a crucial downstream partner of group I metabotropic glutamate receptor signaling in dorsal horn neurons.
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DOI：
10.1097/j.pain.0000000000002396
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发表时间：
2022-04-01
期刊：
影响因子：
7.4
通讯作者：
Hu H
中科院分区：
文献类型：
--
作者：
Xia J;Dou Y;Mei Y;Munoz FM;Gao R;Gao X;Li D;Osei-Owusu P;Schiffenhaus J;Bekker A;Tao YX;Hu H
I组代谢性谷氨酸受体(mGluR1和mGluR5，mGluR1/5)与包括慢性疼痛在内的多种中枢神经系统疾病有关。众所周知，mGluR1/5的激活会导致三磷酸肌醇(IP3)和二酰甘油(DAG)的产生，从而激活细胞外信号调节激酶(ERK1/2)，增加神经元的兴奋性，但mGluR1/5是如何介导这一过程的尚不清楚。我们以前报道过Orai1负责钙库操作的钙内流(SOCE)，并在中枢敏化中起关键作用。然而，Orai1是如何在生理条件下被激活的尚不清楚。在这里，我们测试了假设，mGluR1/5招募Orai1作为其下游信号通路的一部分，在背角神经元。我们证明神经递质谷氨酸诱导STIM1斑点的形成不是由NMDA或AMPA受体介导的。在Orai1缺乏的神经元中，在NMDA/AMPA受体拮抗剂存在下，谷氨酸诱导的钙内流被消除。DHPG(mGluR1/5的激动剂)诱导的钙内流可被Orai1缺乏所消除，但不受TRPC1或TRPC3下调的影响。在培养的Orai1缺陷神经元中，DHPG诱导的ERK1/2的激活和神经元兴奋性的调节被取消。此外，在Orai1基因缺陷小鼠中，DHPG诱导的伤害行为明显减少。我们的发现揭示了以前未知的Orai1和mGluR1/5之间的功能偶联，并阐明了mGluR1/5介导的神经元可塑性的机制。
Group I metabotropic glutamate receptors (mGluR1 and mGluR5, mGluR1/5) have been implicated in several CNS diseases including chronic pain. It is known that activation of mGluR1/5 results in production of inositol triphosphate (IP3) and diacylglycerol (DAG) that leads to activation of extracellular signal-regulated kinases (ERK1/2) and an increase in neuronal excitability, but how mGluR1/5 mediate this process remains unclear. We previously reported that Orai1 is responsible for store-operated calcium entry (SOCE) and plays a key role in central sensitization. However, how Orai1 is activated under physiological conditions is unknown. Here, we tested the hypothesis that mGluR1/5 recruit Orai1 as part of its downstream signaling pathway in dorsal horn neurons. We demonstrate that neurotransmitter glutamate induces STIM1 puncta formation, which is not mediated by NMDA or AMPA receptors. Glutamate-induced Ca2+ entry in the presence of NMDA/AMPA receptor antagonists is eliminated in Orai1-deficient neurons. DHPG (an agonist of mGluR1/5)-induced Ca2+ entry is abolished by Orai1 deficiency, but not affected by knocking down of TRPC1 or TRPC3. DHPG-induced activation of ERK1/2 and modulation of neuronal excitability are abolished in cultured Orai1-deficient neurons. Moreover, DHPG-induced nociceptive behavior is markedly reduced in Orai1-deficient mice. Our findings reveal previously unknown functional coupling between Orai1 and mGluR1/5 and shed light on the mechanism underlying mGluR1/5-mediated neuronal plasticity.
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DOI：
10.1523/jneurosci.5053-10.2011
发表时间：
2011-03-09
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Gemes G;Bangaru ML;Wu HE;Tang Q;Weihrauch D;Koopmeiners AS;Cruikshank JM;Kwok WM;Hogan QH
通讯作者：
Hogan QH
影响因子：
8
作者：
Muik, Martin;Schindl, Rainer;Fahrner, Marc;Romanin, Christoph
通讯作者：
Romanin, Christoph
影响因子：
4.8
作者：
He, LP;Hewavitharana, T;Gill, DL
通讯作者：
Gill, DL
氯硝柳胺是 I 类代谢型谷氨酸受体的负变构调节剂：对神经性疼痛的影响
影响因子：
3.7
作者：
Ai, Ni;Wood, Richard D.;Welsh, William J.
通讯作者：
Welsh, William J.
影响因子：
7.3
作者：
Harper, Matthew T.;Londono, Juan E. Camacho;Poole, Alastair W.
通讯作者：
Poole, Alastair W.