Metabotropic signaling downstream of GABAA receptors suppresses neuroinflammation in Parkinson's disease

  • NPJ Parkinsons Dis. 2026 Jun 6. doi: 10.1038/s41531-026-01425-5.
Wenjing Lu  #  1  2 ,  Lirong Zhang  #  2  3 ,  Xi Chen  3 ,  Xiaoxi Ren  2  3 ,  Fenqin Xue  4 ,  Feilong Zhang  2  3 ,  Jing Sun  5 ,  Wei Wang  1 ,  Haixia Huang  6  7 ,  Jianliang Zhang  8  9
Affiliations
  • 1. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
  • 2. Laboratory for Clinical Medicine, Capital Medical University, Beijing, China.
  • 3. Department of Neurobiology, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing, China.
  • 4. Core Facilities Center, Capital Medical University, Beijing, China.
  • 5. Department of Pathology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
  • 6. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China. [email protected].
  • 7. Laboratory for Clinical Medicine, Capital Medical University, Beijing, China. [email protected].
  • 8. Laboratory for Clinical Medicine, Capital Medical University, Beijing, China. [email protected].
  • 9. Department of Neurobiology, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 42251036 DOI: 10.1038/s41531-026-01425-5
Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disorder, in which persistent neuroinflammation has been recognized as a major pathological component. Thus, strategies aimed at suppressing neuroinflammation are particularly important for developing disease-modifying therapies in PD. In this study, we examined the role of gamma-aminobutyric acid Type A Receptors (GABAARs) in regulating microglial activation and neuroinflammation, and their implications for neuroprotection in a lipopolysaccharide (LPS)-induced PD model. We confirmed that stimulation of GABAARs markedly inhibited neuroinflammation and consequently attenuated related neurotoxicity both in vitro and in vivo. Mechanistic investigations revealed that metabotropic signaling cascades downstream of GABAARs in microglia were involved, including intracellular calcium release and the mobilization of phosphatases, which dephosphorylated IκBα and restricted nuclear translocation of p65, thereby exerting anti-inflammatory effects. Moreover, pharmacological and immunoprecipitation assays showed that Phospholipase C (PLC) physically interacted with GABAARs and mediated calcium release from intracellular stores. These metabotropic signaling mechanisms underlie the suppressive action of GABAARs on LPS-induced neuroinflammation. Given the central role of neuroinflammation in PD pathogenesis and Other neurodegenerative conditions, this study provides new insights into the therapeutic potential of targeting GABAARs to combat neuroinflammation and neurodegeneration in PD.

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