PD-1 Regulates GABAergic Neurotransmission and GABA-Mediated Analgesia and Anesthesia.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Jiang, C; Wang, Z; Donnelly, CR; Wang, K; Andriessen, AS; Tao, X; Matsuda, M; Zhao, J; Ji, R-R

Published Date

  • October 23, 2020

Published In

Volume / Issue

  • 23 / 10

Start / End Page

  • 101570 -

PubMed ID

  • 33083737

Pubmed Central ID

  • PMC7530307

Electronic International Standard Serial Number (EISSN)

  • 2589-0042

Digital Object Identifier (DOI)

  • 10.1016/j.isci.2020.101570

Language

  • eng

Conference Location

  • United States