PD-1 Regulates GABAergic Neurotransmission and GABA-Mediated Analgesia and Anesthesia
Summary: 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 repor...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-10-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004220307628 |
| _version_ | 1818347488319373312 |
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| author | Changyu Jiang Zilong Wang Christopher R. Donnelly Kaiyuan Wang Amanda S. Andriessen Xueshu Tao Megumi Matsuda Junli Zhao Ru-Rong Ji |
| author_facet | Changyu Jiang Zilong Wang Christopher R. Donnelly Kaiyuan Wang Amanda S. Andriessen Xueshu Tao Megumi Matsuda Junli Zhao Ru-Rong Ji |
| author_sort | Changyu Jiang |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-12-13T17:34:57Z |
| format | Article |
| id | doaj.art-76f0639f4d134c209b18c1d83305e22d |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-13T17:34:57Z |
| publishDate | 2020-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-76f0639f4d134c209b18c1d83305e22d2022-12-21T23:36:57ZengElsevieriScience2589-00422020-10-012310101570PD-1 Regulates GABAergic Neurotransmission and GABA-Mediated Analgesia and AnesthesiaChangyu Jiang0Zilong Wang1Christopher R. Donnelly2Kaiyuan Wang3Amanda S. Andriessen4Xueshu Tao5Megumi Matsuda6Junli Zhao7Ru-Rong Ji8Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USACenter for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USACenter for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USACenter for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USACenter for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USACenter for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USACenter for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USACenter for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USACenter for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA; Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004220307628ImmunologyMolecular BiologyNeuroscience |
| spellingShingle | Changyu Jiang Zilong Wang Christopher R. Donnelly Kaiyuan Wang Amanda S. Andriessen Xueshu Tao Megumi Matsuda Junli Zhao Ru-Rong Ji PD-1 Regulates GABAergic Neurotransmission and GABA-Mediated Analgesia and Anesthesia iScience Immunology Molecular Biology Neuroscience |
| title | PD-1 Regulates GABAergic Neurotransmission and GABA-Mediated Analgesia and Anesthesia |
| title_full | PD-1 Regulates GABAergic Neurotransmission and GABA-Mediated Analgesia and Anesthesia |
| title_fullStr | PD-1 Regulates GABAergic Neurotransmission and GABA-Mediated Analgesia and Anesthesia |
| title_full_unstemmed | PD-1 Regulates GABAergic Neurotransmission and GABA-Mediated Analgesia and Anesthesia |
| title_short | PD-1 Regulates GABAergic Neurotransmission and GABA-Mediated Analgesia and Anesthesia |
| title_sort | pd 1 regulates gabaergic neurotransmission and gaba mediated analgesia and anesthesia |
| topic | Immunology Molecular Biology Neuroscience |
| url | http://www.sciencedirect.com/science/article/pii/S2589004220307628 |
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