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 5

Injection i.t. or i.g. of MaR1 reduces neuropathic pain via GPR37L1 expressed on SGCs.

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Injection i.t. or i.g. of MaR1 reduces neuropathic pain via GPR37L1 expr...
(A and B) MaR1 injected i.t. (100 ng) reduces mechanical allodynia in Gpr37l1+/+ and Gpr37l1+/– mice induced by 75 mg/kg of STZ and 6 mg/kg of PTX. (A) Paw withdrawal thresholds were assessed in Gpr37l1+/+ mice (left, n = 7), Gpr37l1+/– mice (middle, n = 10), and Gpr37l1–/– mice (n = 8) after i.t. MaR1 injection in the STZ model. (B) Paw withdrawal thresholds in Gpr37l1+/+ mice (left, n = 5), Gpr37l1+/– mice (middle, n = 7), and Gpr37l1–/– mice (n = 6) after i.t. MaR1 injection in the PTX model. Behavior was assessed 1 hour after MaR1 injection on post-PTX and post-STZ day 3. (C) Upper panel, schematic of i.g. injection. Lower panel, knockdown of Gpr37l1 expression in the L4 DRGs after siRNA treatment compared with scRNA treatment (n = 8). (D) Injection of MaR1 (i.g., 10 ng, 2 µl) reduces PTX-induced mechanical allodynia in control animals treated with scRNA, but not in animals treated with Gpr37l1 siRNA (n = 10). (E) MaR1 inhibits PTX-induced IL-1β release in SGC-neuron cocultures via GPR37L1. IL-1β release in cocultures from DRG of WT mice (n = 6) and Gpr37l1–/– mice (n = 6) was analyzed by ELISA. The cultures were stimulated with 1 μM PTX for 24 hours in the absence or presence of MaR1 (100 nM). Data are expressed as means ± SEM and were statistically analyzed by paired t test (A and B), 2-way ANOVA with Bonferroni’s post hoc test (D and E), Tukey’s post hoc test (D and E), or unpaired t test (C). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.