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The GABAB receptor mediates neuroprotection by coupling to G13

Yunyun Wang1, Siyu Gai1, Wenhua Zhang1

  • 1Cellular Signaling laboratory, International Research Center for Sensory Biology and Technology of MOST, Key Laboratory of Molecular Biophysics of MOE, School of Life Science and Technology, Huazhong University of Science and Technology, 430074 Wuhan, China.

Science Signaling
|October 19, 2021
PubMed

Insights

GABAB receptors activate MAPK pathways independently of β-arrestins. A novel G13-mediated pathway involving RhoA/Rac1 and JNK promotes neuroprotection, working alongside a known Gi/o pathway.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Molecular Biology

Background:

  • G protein–coupled receptors (GPCRs) regulate cell functions via mitogen-activated protein kinase (MAPK) pathways.
  • β-Arrestins typically mediate GPCR-MAPK signaling, but not for the GABAB receptor (GABABR).
  • GABABR, when coupled to Gi/o, activates ERK1/2 kinases.

Purpose of the Study:

  • To uncover a distinct β-arrestin–independent mechanism of MAPK pathway activation by GABABR.
  • To elucidate the role of G13 in GABABR-mediated signaling.
  • To investigate the contribution of this novel pathway to neuroprotection.

Main Methods:

  • Utilized primary mouse neurons to study GABABR signaling.
  • Investigated the activation of small guanosine triphosphatases (GTPases) RhoA and Rac1.
  • Assessed the phosphorylation and accumulation of PSD95 and GABABR-mediated neuroprotection.

Main Results:

  • Discovered a β-arrestin–independent pathway where GABABR activates JNK via G13, RhoA, and Rac1.
  • This pathway promotes PSD95 phosphorylation and accumulation, contributing to neuroprotection.
  • The G13-JNK pathway synergizes with the known Gi/o-ERK pathway for enhanced neuroprotection.
  • G13 activation by GABABR agonists shows slower kinetics and lower potency compared to Gi/o activation.

Conclusions:

  • GABABR employs distinct, β-arrestin–independent mechanisms for MAPK activation.
  • G13-mediated signaling represents a novel pathway for GABABR function.
  • These synergistic pathways contribute to GABABR-mediated neuroprotection in a context-specific manner.

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