Related Experiment Video

Updated: Jun 5, 2025

Inhibitory Synapse Formation in a Co-culture Model Incorporating GABAergic Medium Spiny Neurons and HEK293 Cells Stably Expressing GABAA Receptors
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Inhibitory Synapse Formation in a Co-culture Model Incorporating GABAergic Medium Spiny Neurons and HEK293 Cells Stably Expressing GABAA Receptors

Published on: November 14, 2014

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GABAA receptor π forms channels that stimulate ERK through a G-protein-dependent pathway

Yueyue Wang1, Yalan Zhang2, Wenxue Li3

  • 1Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA; Breast Medical Oncology, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA.

Molecular Cell
|December 6, 2024
PubMed

Insights

The γ-aminobutyric acid type-A receptor subunit π (GABRP) activates cancer growth via G-protein-coupled pathways, not direct ion flow. Understanding its structure and function offers new cancer treatment targets.

Area of Science:

  • Molecular and Cellular Biology
  • Cancer Research
  • Neuroscience

Background:

  • The γ-aminobutyric acid type-A receptor subunit π (GABRP) is implicated in cancer growth.
  • Its signaling pathway, particularly through extracellular-regulated kinase (ERK), remains uncharacterized.

Purpose of the Study:

  • To determine the structural and functional mechanisms of GABRP signaling in cancer.
  • To elucidate the pathway through which GABRP stimulates cancer growth.

Main Methods:

  • Cryoelectron microscopy (cryo-EM) was used to determine the structures of GABRP in native nanodiscs.
  • Functional assays were performed to assess GABRP's response to GABA binding.

Main Results:

  • GABRP forms homopentamers structurally similar to other GABAARs, transitioning between closed and open states.
  • GABRP primarily signals through a G-protein-coupled pathway to activate ERK, not via chloride flux at physiological GABA levels.
  • Ionotropic activity was observed only at supraphysiological GABA concentrations.

Conclusions:

  • GABRP functions akin to a metabotropic receptor, distinct from typical ionotropic GABAARs.
  • The study provides a structural and functional basis for targeting GABRP in GABRP-positive cancers.
  • Decoupling GABRP's growth signaling from its ionotropic function opens new therapeutic strategies.
Keywords:
ERKGABAGABA type-A receptorGABA(A) receptor πGABRPMAPKTNBCantibodybreast cancercancertherapeutics

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