Activation of a dimeric metabotropic glutamate receptor by intersubunit rearrangement.
Although many G protein-coupled receptors (GPCRs) can form dimers, a possible role of this phenomenon in their activation remains elusive. A recent and exciting proposal is that a dynamic intersubunit interplay may contribute to GPCR activation. Here, we examined this possibility using dimeric metabotropic glutamate receptors (mGluRs). We first developed a system to perfectly control their subunit composition and show that mGluR dimers do not form larger oligomers. We then examined an mGluR dimer containing one subunit in which the extracellular agonist-binding domain was uncoupled from the G protein-activating transmembrane domain. Despite this uncoupling in one protomer, agonist stimulation resulted in symmetric activation of either transmembrane domain in the dimer with the same efficiency. This, plus other data, can only be explained by an intersubunit rearrangement as the activation mechanism. Although well established for other types of receptors such as tyrosine kinase and guanylate cyclase receptors, this is the first clear demonstration that such a mechanism may also apply to GPCRs.
Brock
Carsten
C
University of Montpellier 1 and 2, CNRS UMR 5203, Institute of Functional Genomics, 141 rue de la Cardonille, Montpellier, France.
Oueslati
Nadia
N
Soler
Stéphan
S
Boudier
Laure
L
Rondard
Philippe
P
Pin
Jean-Philippe
JP
D000595:Amino Acid Sequence; D002460:Cell Line; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
D021122:Protein Subunits; D018094:Receptors, Metabotropic Glutamate