Satellite glial GPR37L1 and its ligand maresin 1 regulate potassium channel signaling and pain homeostasis
Sangsu Bang, … , Luda Diatchenko, Ru-Rong Ji
Sangsu Bang, … , Luda Diatchenko, Ru-Rong Ji
Published March 26, 2024
Citation Information: J Clin Invest. 2024;134(9):e173537. https://doi.org/10.1172/JCI173537.
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Research Article Neuroscience

Satellite glial GPR37L1 and its ligand maresin 1 regulate potassium channel signaling and pain homeostasis

Abstract

G protein–coupled receptor 37-like 1 (GPR37L1) is an orphan GPCR with largely unknown functions. Here, we report that Gpr37l1/GRP37L1 ranks among the most highly expressed GPCR transcripts in mouse and human dorsal root ganglia (DRGs) and is selectively expressed in satellite glial cells (SGCs). Peripheral neuropathy induced by streptozotoxin (STZ) and paclitaxel (PTX) led to reduced GPR37L1 expression on the plasma membrane in mouse and human DRGs. Transgenic mice with Gpr37l1 deficiency exhibited impaired resolution of neuropathic pain symptoms following PTX- and STZ-induced pain, whereas overexpression of Gpr37l1 in mouse DRGs reversed pain. GPR37L1 is coexpressed with potassium channels, including KCNJ10 (Kir4.1) in mouse SGCs and both KCNJ3 (Kir3.1) and KCNJ10 in human SGCs. GPR37L1 regulates the surface expression and function of the potassium channels. Notably, the proresolving lipid mediator maresin 1 (MaR1) serves as a ligand of GPR37L1 and enhances KCNJ10- or KCNJ3-mediated potassium influx in SGCs through GPR37L1. Chemotherapy suppressed KCNJ10 expression and function in SGCs, which MaR1 rescued through GPR37L1. Finally, genetic analysis revealed that the GPR37L1-E296K variant increased chronic pain risk by destabilizing the protein and impairing the protein’s function. Thus, GPR37L1 in SGCs offers a therapeutic target for the protection of neuropathy and chronic pain.

Authors

Sangsu Bang, Changyu Jiang, Jing Xu, Sharat Chandra, Aidan McGinnis, Xin Luo, Qianru He, Yize Li, Zilong Wang, Xiang Ao, Marc Parisien, Lorenna Oliveira Fernandes de Araujo, Sahel Jahangiri Esfahani, Qin Zhang, Raquel Tonello, Temugin Berta, Luda Diatchenko, Ru-Rong Ji

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Figure 3

GPR37L1 is dysregulated in pain and protects against neuropathic pain.

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GPR37L1 is dysregulated in pain and protects against neuropathic pain. (...
(A and B) Neuropathic pain (mechanical allodynia) induced by STZ (75 mg/kg) and PTX (6 mg/kg) in WT and Gpr37l1 mutant mice. (A) Time course of STZ (75mg/kg)-induced mechanical allodynia in Gpr37l1+/+ mice (n = 5), Gpr37l1+/– mice (n = 7), and Gpr37l1–/– mice (n = 6). (B) Time course of PTX (6 mg/kg)-induced mechanical allodynia in Gpr37l1+/+ mice (n = 7), Gpr37l1+/– mice (n = 10), and Gpr37l1–/– mice (n = 8). (C and D) GPR37L1 expression in PM fraction of DRG tissues of control mice and mice with STZ treatment (n = 3). Transferrin (TfR) was used as a loading control from a parallel gel. (D) Quantification of GPR37L1. (E–G) Unilateral i.g. microinjection of Gpr37l1-targeting siRNA reduces Gpr37l1 expression and induces persistent mechanical allodynia in naive animals. (E) Schematic of i.g. microinjection of siRNA or scRNA in the L4 and L5 DRGs, followed by von Frey testing and tissue collection for quantitative reverse-transcription PCR (RT-PCR) analysis. (F) Mechanical allodynia is induced by siRNA (n = 10), not scRNA (n = 10). (G) RT-PCR analyses of Gpr37l1 in DRGs (n = 10 mice). (H–J) Unilateral i.g. microinjection of Fabp7-Gpr37l1 (AAV-L1) or Fabp7-mock AAV virus (AAV-Con) rescued Gpr37l1 expression and reduced persistent mechanical allodynia in CIPN mice (6 mg/kg PTX). (H) Schematic of i.g. microinjection of AAV virus in the L4 and L5 DRGs, given 1 week after PTX, followed by von Frey testing and tissue collection for RT-qPCR analysis. (I) PTX-mediated mechanical allodynia is reduced by AAV-L1 application (n = 8) but not AAV-Con (n = 8). (J) RT-PCR analyses showing expression of Gpr37l1 (n = 4 mice). Data are represented as mean ± SEM and statistically analyzed by 2-way ANOVA with Tukey’s post hoc test (A, B, and I) or Bonferroni’s post hoc test (F), 1-way ANOVA with Tukey’s post hoc test (G and J), and 2-tailed t test (D). *P < 0.05; **P < 0.01; ****P < 0.0001.