Yueyue Wang, Yalan Zhang, Wenxue Li, Barbora Salovska, Jianan Zhang, Tongqing Li, Hengyi Li, Yansheng Liu, Leonard K. Kaczmarek, Lajos Pusztai, Daryl E. Klein
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引用次数: 0
Abstract
The rare γ-aminobutyric acid type-A receptor (GABAAR) 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 GABAAR 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.
期刊介绍:
Molecular Cell is a companion to Cell, the leading journal of biology and the highest-impact journal in the world. Launched in December 1997 and published monthly. Molecular Cell is dedicated to publishing cutting-edge research in molecular biology, focusing on fundamental cellular processes. The journal encompasses a wide range of topics, including DNA replication, recombination, and repair; Chromatin biology and genome organization; Transcription; RNA processing and decay; Non-coding RNA function; Translation; Protein folding, modification, and quality control; Signal transduction pathways; Cell cycle and checkpoints; Cell death; Autophagy; Metabolism.