8VSZ

CryoEM structure of human GABAA receptor pi (GABRP) apo state

Summary for 8VSZ

• Entry DOI: 10.2210/pdb8vsz/pdb
• EMDB information: 43512
• Descriptor: Gamma-aminobutyric acid receptor subunit pi, alpha-D-mannopyranose-(1-4)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: cryo-em, gabaa receptor, channel, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 5
• Total formula weight: 258279.12

Authors

Wang, Y.,Klein, D. (deposition date: 2024-01-25, release date: 2024-12-11, Last modification date: 2026-01-07)

Primary citation

Wang, Y.,Zhang, Y.,Li, W.,Salovska, B.,Zhang, J.,Li, T.,Li, H.,Liu, Y.,Kaczmarek, L.K.,Pusztai, L.,Klein, D.E.
GABA A receptor pi forms channels that stimulate ERK through a G-protein-dependent pathway.
Mol.Cell, 85:166-176.e5, 2025

PubMed Abstract: The rare γ-aminobutyric acid type-A receptor (GABAR) 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 GABAR 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.

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

Experimental method

ELECTRON MICROSCOPY (3.07 Å)