Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Neuroscience Article has an altmetric score of 3

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

  • Text
  • PDF
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

×

Figure 7

GPR37L1 regulates KCNJ3/GIRK1 signaling in human SGCs.

Options: View larger image (or click on image) Download as PowerPoint
GPR37L1 regulates KCNJ3/GIRK1 signaling in human SGCs.
(A and B) Single-...
(A and B) Single-cell RNA-Seq meta-analysis of KCNJ transcript expression in mouse (A) and human (B) TGs from a published database (36). (A) Mouse SGCs predominantly express Gpr37l1 and Kcnj10, which are clustered together. (B) Human SGCs express GPR37L1, KCNJ3, and KCNJ10, which are clustered together. Note greater expression of KCNJ3 than KCNJ10. (C) Transcriptomic meta-analysis of human DRGs, from a published database (29), reveals downregulations of GPR37L1 and KCNJ3, but not KCNJ10, in patients with painful DPN. (D) Triple RNAscope ISH showing the expression of KCNJ10 (red), KCNJ3 mRNA (white), and TUBB3 (green) in nondiseased human DRGs. Note colocalization of KCNJ10 and KCNJ3 in SGCs surrounding the TUBB3+ neurons. Scale bar: 50 μm. (E) Western blots showing PM fractions of KCNJ3 levels in human DRGs of neuropathic pain patients and controls from parallel gels. (F) Quantification of the Western blot results in E (n = 4). (G and H) MaR1 increases K+ levels in human SGCs. (G) Images of Ti+ influx in human DRG cocultures for SGCs and neurons treated with vehicle and MaR1. SGCs are indicated with white arrows. *: neuron, 20x magnification. Scale bar: 50 μm. (H) Quantification of fluorescence intensity for G at 10 minutes after 500 μM Ti+ simulation in human SGCs. n = 5 cultures from 2 donors. (I) Time course of Ti+ influx in HEK293 cells expressing GPR37L1 with vehicle (n = 16) or MaR1 (100 nM, 30 minutes n = 16) and GPR37L1/KCNJ3 in the presence of vehicle (n = 13) and MaR1 (100 nM, 30 minutes, n = 12). (J) Quantification of Ti+ influx in I after 10 minutes of 500 μM Ti+ stimulation (n = 6 culture). Data are expressed as means ± SEM and were analyzed by 2-tailed t test (C, F, and H) or 1-way ANOVA with Tukey’s post hoc test (J). *P < 0.05; **P < 0.01; ***P < 0.001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 4 X users
10 readers on Mendeley
See more details