Summary
For a long time, G-protein coupled receptors (GPCRs) were widely considered to be monomeric entities. However, within the last ten years, increasing amounts of data support the idea that GPCRs can form dimers, either homodimers or heterodimers (Bouvier 2001). Such an observation has raised a number of important issues concerning the activation process: what is the stoichiometry required for the dimer activation? Is one agonist per dimer sufficient? Should both heptahelical domains (HD) be in an active conformation? Here, these issues are examined using the metabotropic glutamate receptors (mGlu receptors), the GPCRs activated by the neurotransmitter glutamate, as a model system. These receptors are constitutive homodimers linked by a disulfide bridge, each subunit being composed of two main domains: a “Venus Flytrap” extracellular domain (VFT) where glutamate binds, and a HD that is common to all GPCRs and is responsible for G-protein activation. Using a strategy allowing perfect control of the subunit composition in a mGlu dimer, we showed that a single agonist per dimer is sufficient for activation but that two agonists are required to reach the full activity. Moreover, thanks to artificial ligands that bind directly into the HDs and stabilize either their active or inactive conformation, we also demonstrated that a single HD per dimer is activated at a time. Such an asymmetric functioning of homodimeric proteins appears surprising. We propose that this phenomenon is also valid for many other GPCRs and results from their association with an asymmetric protein, the heterotrimeric G-protein.
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Pin, J.P. et al. (2006). Dimeric GPCRs: what did we learn from the metabotropic glutamate receptors?. In: Conn, M., Kordon, C., Christen, Y. (eds) Insights into Receptor Function and New Drug Development Targets. Research and Perspectives in Endocrine Interactions. Springer, Berlin, Heidelberg . https://doi.org/10.1007/3-540-34447-0_7
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DOI: https://doi.org/10.1007/3-540-34447-0_7
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