期刊
NEURON
卷 92, 期 1, 页码 143-159出版社
CELL PRESS
DOI: 10.1016/j.neuron.2016.08.036
关键词
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资金
- National Institutes of Health Nanomedicine Center for the Optical Control of Biological Function [2PN2EY018241]
- National Science Foundation Major Research Instrumentation Award [1041078]
- EAGER award [IOS-1451027]
- [S10 RR028971]
- Direct For Biological Sciences [1451027] Funding Source: National Science Foundation
- Division Of Integrative Organismal Systems [1451027] Funding Source: National Science Foundation
- Div Of Biological Infrastructure
- Direct For Biological Sciences [1041078] Funding Source: National Science Foundation
G protein-coupled receptors (GPCRs) mediate cellular responses to a wide variety of extracellular stimuli. GPCR dimerization may expand signaling diversity and tune functionality, but little is known about the mechanisms of subunit assembly and interaction or the signaling properties of heteromers. Using single-molecule subunit counting on class C metabotropic glutamate receptors (mGluRs), we map dimerization determinants and define a heterodimerization profile. Intersubunit fluorescence resonance energy transfer measurements reveal that interactions between ligand-binding domains control the conformational rearrangements underlying receptor activation. Selective liganding with photo-switchable tethered agonists conjugated to one or both subunits of covalently linked mGluR2 homodimers reveals that receptor activation is highly cooperative. Strikingly, this cooperativity is asymmetric in mGluR2/mGluR3 heterodimers. Our results lead to a model of cooperative activation of mGluRs that provides a framework for understanding how class C GPCRs couple extracellular binding to dimer reorganization and G protein activation.
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