Authors
Randal A Serafini, Bruno Giotti, Alex Luebbers, Kerri D Pryce, Ilinca M Giosan, Madden J Tuffy, Jeffrey Zimering, Aarthi Ramakrishan, Donghoon Lee, Ekaterina Kintsurashvili, Feodora L Bertherat, Neelakshi Patne, John F Fullard, Panos Roussos, Li Shen, Mikel Garcia-Marcos, Alexander M Tsankov, Venetia Zachariou
Published in
Science signaling. Volume 19. Issue 958. Pages eaed7175. Oct 06, 2026. Epub Oct 06, 2026.
Abstract
Regulator of G protein signaling 4 (RGS4) is a Gα subunit-interacting protein that modulates the functional responses of various G protein-coupled receptors (GPCRs) and that is present in several components of the nociceptive circuitry. Here, we found that RGS4 in lumbar dorsal root ganglia (DRGs) is required for the maintenance of chronic pain states in mice. Rgs4 knockout in Mrgprd+ nonpeptidergic C-fibers was sufficient to attenuate sensory hypersensitivity in several acute and chronic injury models without affecting acute nociceptive responses. Single-nucleus RNA sequencing in ipsilateral lumbar DRGs from mice with prolonged peripheral nerve injury identified cell subset-specific gene expression changes in Rgs4 knockout mice after recovery from mechanical hypersensitivity, including Gabbr2, which encodes the GABAB receptor, in Mrgprd+ fibers. RGS4 competed with Gαi-interacting protein (GINIP) to modulate GABAB receptor signaling, which suppresses neuronal excitability. Analysis of genetically modified mice suggested that imbalances in the interplay between RGS4 and GINIP contribute to the maintenance of sensory hypersensitivity and chronic pain states. Overall, our study reveals critical G protein-modulatory pathways in the DRG that promote the maintenance of sensory hypersensitivity in chronic pain models.
PMID:
42837443
Bibliographic data and abstract were imported from PubMed on 07 Oct 2026.
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