Nanobody-based sensors reveal a high proportion of mGlu heterodimers in the brain

Jiyong Meng, Chanjuan Xu, Pierre André Lafon, Salomé Roux, Michaël Mathieu, Rui Zhou, Pauline Scholler, Emilie Blanc, Jérôme A.J. Becker, Julie Le Merrer, Javier González-Maeso, Patrick Chames, Jianfeng Liu, Jean Philippe Pin, Philippe Rondard

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Membrane proteins, including ion channels, receptors and transporters, are often composed of multiple subunits and can form large complexes. Their specific composition in native tissues is difficult to determine and remains largely unknown. In this study, we developed a method for determining the subunit composition of endogenous cell surface protein complexes from isolated native tissues. Our method relies on nanobody-based sensors, which enable proximity detection between subunits in time-resolved Förster resonance energy transfer (FRET) measurements. Additionally, given conformation-specific nanobodies, the activation of these complexes can be recorded in native brain tissue. Applied to the metabotropic glutamate receptors in different brain regions, this approach revealed the clear existence of functional metabotropic glutamate (mGlu)2–mGlu4 heterodimers in addition to mGlu2 and mGlu4 homodimers. Strikingly, the mGlu4 subunits appear to be mainly heterodimers in the brain. Overall, these versatile biosensors can determine the presence and activity of endogenous membrane proteins in native tissues with high fidelity and convenience. [Figure not available: see fulltext.]

Original languageEnglish
Pages (from-to)894-903
Number of pages10
JournalNature Chemical Biology
Issue number8
StatePublished - Aug 2022
Externally publishedYes


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