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 6

MaR1 increases surface expression of GPR37L1 and KCNJ10/Kir4.1 and regulates K+ currents in SGCs via GPR37L1.

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MaR1 increases surface expression of GPR37L1 and KCNJ10/Kir4.1 and regul...
(A–C) Western blot analysis of surface GPR37L1 in whole-mount DRG. (A) Schematic of whole-mount DRG treatment with PTX or MaR1, followed by PM preparation and Western blot. (B) Western blot showing effects of PTX (1 μM) and MaR1 (100 ng/ml, 2 hours) on PM and total fraction of GPR37L1. (C) Quantification of GRP37L1 expression (n = 6 preps). (D–J) Patch-clamp recordings of K+ currents in SGCs in whole-mount DRG. (D) Micrograph showing patch-clamp recording in SGC (red arrow). Scale bar: 10 μm. (E) Representative trace for total K+ currents in SGCs. (F) Average current-voltage (I/V) curves in SGCs treated with vehicle (n = 5 cells) and PTX (1 μM, n = 18 cells). (G) Quantification of amplitude of K+ currents (Ik-160). (H) Representative traces for total K+ currents in SGCs of Gpr37l1+/+ or Gpr37l1+/– DRGs treated with PTX (1 μM, 1 hour) or PTX plus MaR1 (100 ng/ml, 1 hour) or in Gpr37l1+/– DRGs. (I) Average I/V curves in WT SGCs after treatment with PTX (n = 18 cells) or PTX plus MaR1 (n = 15 cells). (J) Amplitude of Κ+ currents (Ik-160) for H and I. Gpr37l1+/– DRG preps: n = 17 for PTX; n = 14 for PTX plus MaR1. (K) Triple IHC staining colocalization of GPR37L1 (green), GS (white), and KCNJ10 (red) in mouse DRG SGCs. Scale bar: 25 μm. (L) Protein pull-down and Co-IP show GPR37L1 and KCNJ10 interaction in mouse DRGs from parallel gels. (M) Quantification of pull-down results in L for GPR37L1 and KCNJ10. n = 5 mice. (N) Dose-response curve of Ti+ influx based on AUC using Richard’s 5-parameter methods (10 minutes, n = 6). Data are expressed as mean ± SEM and were analyzed by 2-way ANOVA with Bonferroni’s post hoc test (F, I, and J), 1-way ANOVA with Tukey’s post hoc test (C and M), or 2-tailed t test (G). *P < 0.05; **P < 0.01; ***P < 0.001.