Mechanism of Assembly and Cooperativity of Homomeric and Heteromeric Metabotropic Glutamate Receptors

Joshua Levitz, Chris Habrian, Shashank Bharill, Zhu Fu, Reza Vafabakhsh, Ehud Y. Isacoff*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

77 Scopus citations


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 photoswitchable 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.

Original languageEnglish (US)
Pages (from-to)143-159
Number of pages17
Issue number1
StatePublished - Oct 5 2016

ASJC Scopus subject areas

  • Neuroscience(all)


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