PD-1 Regulates GABAergic Neurotransmission and GABA-Mediated Analgesia and Anesthesia.
PD-1 Regulates GABAergic Neurotransmission and GABA-Mediated Analgesia and Anesthesia.
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PD-1调节GABA能神经传递和GABA介导的镇痛和麻醉。
DOI：
10.1016/j.isci.2020.101570
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发表时间：
2020-10-23
期刊：
影响因子：
5.8
通讯作者：
Ji RR
中科院分区：
文献类型：
--
作者：
Jiang C;Wang Z;Donnelly CR;Wang K;Andriessen AS;Tao X;Matsuda M;Zhao J;Ji RR
免疫检查点抑制因子程序性细胞死亡蛋白1(PD-1)在免疫调节中起着重要作用。最近的研究表明，PD-1在外周感觉神经元中的功能性表达，与神经元的兴奋性、疼痛和阿片类止痛有关。在这里，我们报告了PD-1在中枢神经系统(CNS)中的神经元表达和功能，包括脊髓、丘脑和大脑皮层。值得注意的是，脊髓切片、脑片和分离的皮质神经元中的PD-1中和免疫治疗Nivolumab抑制了脊髓背角神经元、丘脑神经元和皮质神经元中GABA诱导的电流。在pd1−/−小鼠中，也观察到GABA介导的中枢神经元电流减少，而GABA受体的表达没有变化。从机制上讲，Nivolumab结合脊髓神经元并引起ERK磷酸化以抑制GABA电流。最后，由于缺乏PD1，GABA介导的镇痛和麻醉都受到损害。我们的发现揭示了PD-1是一种中枢神经系统抑制物，调节GABA能信号和GABA介导的行为。PD1基因和PD-1蛋白在脊髓和脑神经元中广泛表达，PD-1受体拮抗剂Nivolumab与神经元PD-1结合诱导ERK激活和GABA能抑制PD1缺乏后GABA介导的痛觉抑制和麻醉受损免疫学；分子生物学；神经科学
The immune checkpoint inhibitor programmed cell death protein 1 (PD-1) plays a critical role in immune regulation. Recent studies have demonstrated functional PD-1 expression in peripheral sensory neurons, which contributes to neuronal excitability, pain, and opioid analgesia. Here we report neuronal expression and function of PD-1 in the central nervous system (CNS), including the spinal cord, thalamus, and cerebral cortex. Notably, GABA-induced currents in spinal dorsal horn neurons, thalamic neurons, and cortical neurons are suppressed by the PD-1-neutralizing immunotherapeutic Nivolumab in spinal cord slices, brain slices, and dissociated cortical neurons. Reductions in GABA-mediated currents in CNS neurons were also observed in Pd1−/− mice without changes in GABA receptor expression. Mechanistically, Nivolumab binds spinal cord neurons and elicits ERK phosphorylation to suppress GABA currents. Finally, both GABA-mediated analgesia and anesthesia are impaired by Pd1 deficiency. Our findings reveal PD-1 as a CNS-neuronal inhibitor that regulates GABAergic signaling and GABA-mediated behaviors. Pd1 mRNA and PD-1 protein are widely expressed in spinal cord and brain neurons GABA-induced currents in CNS neurons are suppressed by PD-1 blockade with Nivolumab Nivolumab binds neuronal PD-1 to induce ERK activation and GABAergic inhibition GABA-mediated pain inhibition and anesthesia is impaired after Pd1 deficiency Immunology ; Molecular Biology; Neuroscience
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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
影响因子：
15.9
作者：
Hebeisen, Michael;Baitsch, Lukas;Rufer, Nathalie
通讯作者：
Rufer, Nathalie
影响因子：
6.2
作者：
Latta-Mahieu, Martine;Elmer, Bradford;Pradier, Laurent
通讯作者：
Pradier, Laurent
影响因子：
82.9
作者：
Baruch, Kuti;Deczkowska, Aleksandra;Schwartz, Michal
通讯作者：
Schwartz, Michal
影响因子：
4.4
作者：
Cerny, Ondrej;Anderson, Karen E.;Sebo, Peter
通讯作者：
Sebo, Peter