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

Yueyue Wang; Yalan Zhang; Wenxue Li; Barbora Salovska; Jianan Zhang; Tongqing Li; Hengyi Li; Yansheng Liu; Leonard K Kaczmarek; Lajos Pusztai; Daryl E Klein

doi:10.1016/j.molcel.2024.11.016

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

Mol Cell. 2024 Nov 28:S1097-2765(24)00921-3. doi: 10.1016/j.molcel.2024.11.016. Online ahead of print.

Authors

Affiliations

¹ Yale 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.
² Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
³ Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
⁴ Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Biomedical Informatics & Data Science, Yale University School of Medicine, New Haven, CT 06510, USA.
⁵ Breast Medical Oncology, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA.
⁶ Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: daryl.klein@yale.edu.

PMID: 39642883
DOI: 10.1016/j.molcel.2024.11.016

Abstract

The rare γ-aminobutyric acid type-A receptor (GABA_AR) subunit π (GABRP) is highly expressed in certain cancers, where it stimulates growth through extracellular-regulated kinase (ERK) signaling by an uncharacterized pathway. To elucidate GABRP's signaling mechanism, we determined cryoelectron microscopy (cryo-EM) structures of GABRP embedded in native nanodiscs, both in the presence and absence of GABA. Structurally, GABRP homopentamers closely resemble heteropentameric GABA_AR anion channels, transitioning from a closed "resting" state to an open "active" state upon GABA binding. However, functional assays reveal that GABRP responds more like a type-B metabotropic receptor. At physiological concentrations of GABA, chloride flux is not detected. Rather, GABRP activates a G-protein-coupled pathway leading to ERK signaling. Ionotropic activity is only triggered at supraphysiological GABA concentrations, effectively decoupling it from GABRP's signaling functions. These findings provide a structural and functional blueprint for GABRP, opening new avenues for targeted inhibition of GABA growth signals in GABRP-positive cancers.

Keywords: ERK; GABA; GABA type-A receptor; GABA(A) receptor π; GABRP; MAPK; TNBC; antibody; breast cancer; cancer; therapeutics.