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| Title | GABA receptor π forms channels that stimulate ERK through a G-protein-dependent pathway. |
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| Journal, issue, pages | Mol Cell, Vol. 85, Issue 1, Page 166-176.e5, Year 2025 |
| Publish date | Jan 2, 2025 |
Authors | Yueyue Wang / Yalan Zhang / Wenxue Li / Barbora Salovska / Jianan Zhang / Tongqing Li / Hengyi Li / Yansheng Liu / Leonard K Kaczmarek / Lajos Pusztai / Daryl E Klein / ![]() |
| 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 ...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. |
External links | Mol Cell / PubMed:39642883 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.07 - 3.1 Å |
| Structure data | EMDB-43512, PDB-8vsz: EMDB-43546, PDB-8vv0: |
| Chemicals | ![]() ChemComp-NAG: ![]() ChemComp-ABU: |
| Source |
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Keywords | MEMBRANE PROTEIN / Cryo-EM / GABAA receptor / Channel / complex |
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homo sapiens (human)
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