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Structures of metabotropic GABA(B) receptor

GABA (γ-aminobutyric acid) stimulation of the metabotropic GABA(B) receptor results in prolonged inhibition of neurotransmission that is central to brain physiology(1). GABA(B) belongs to the Family C of G protein-coupled receptors (GPCRs), which operate as dimers to relay synaptic neurotransmitter...

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Detalles Bibliográficos
Autores principales: Papasergi-Scott, Makaía M., Robertson, Michael J., Seven, Alpay B., Panova, Ouliana, Mathiesen, Jesper M., Skiniotis, Georgios
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429364/
https://www.ncbi.nlm.nih.gov/pubmed/32580208
http://dx.doi.org/10.1038/s41586-020-2469-4
Descripción
Sumario:GABA (γ-aminobutyric acid) stimulation of the metabotropic GABA(B) receptor results in prolonged inhibition of neurotransmission that is central to brain physiology(1). GABA(B) belongs to the Family C of G protein-coupled receptors (GPCRs), which operate as dimers to relay synaptic neurotransmitter signals into a cellular response through the binding and activation of heterotrimeric G proteins(2,3). GABA(B), however, is unique in its function as an obligate heterodimer in which agonist binding and G protein activation take place on distinct subunits(4,5). Here we show structures of heterodimeric and homodimeric full-length GABA(B) receptors. Complemented by cellular signaling assays and atomistic simulations, the structures reveal an essential role for the GABA(B) extracellular loop 2 (ECL2) in relaying structural transitions by ordering the linker connecting the extracellular ligand-binding domain to the transmembrane region. Furthermore, the ECL2 of both GABA(B) subunits caps and interacts with the hydrophilic head of a phospholipid occupying the extracellular half of the transmembrane domain, thereby providing a potentially crucial link between ligand binding and the receptor core that engages G protein. These results provide a starting framework to decipher mechanistic modes of signal transduction mediated by GABA(B) dimers and have important implications for rational drug design targeting these receptors.