Abstract
GPCRs play critical roles in cell communication. Although GPCRs can form heteromers, their role in signaling remains elusive. Here we used rat metabotropic glutamate (mGlu) receptors as prototypical dimers to study the functional interaction between each subunit. mGluRs can form both constitutive homo- and heterodimers. Whereas both mGlu2 and mGlu4 couple to G proteins, G protein activation is mediated by mGlu4 heptahelical domain (HD) exclusively in mGlu2-4 heterodimers. Such asymmetric transduction results from the action of both the dimeric extracellular domain, and an allosteric activation by the partially-activated non-functional mGlu2 HD. G proteins activation by mGlu2 HD occurs if either the mGlu2 HD is occupied by a positive allosteric modulator or if mGlu4 HD is inhibited by a negative modulator. These data revealed an oriented asymmetry in mGlu heterodimers that can be controlled with allosteric modulators. They provide new insight on the allosteric interaction between subunits in a GPCR dimer.
Highlights
Many cell surface receptors form multi-protein complexes for signaling integration (Klingenberg, 1981; Salter, 2003; Altier et al, 2006; Gonzalez-Maeso et al, 2008)
We show that whereas both mGlu2 and mGlu4 heptahelical domain (HD) are capable of activating G proteins, only mGlu4 HD does it in mGlu2-4 heterodimers
We demonstrated that manipulating the conformation of either mGlu2 or mGlu4 HD with positive and negative allosteric modulators can reorient the asymmetry towards mGlu2 activating G proteins
Summary
Many cell surface receptors form multi-protein complexes for signaling integration (Klingenberg, 1981; Salter, 2003; Altier et al, 2006; Gonzalez-Maeso et al, 2008). Whether mGlu heterodimer activation is symmetric or asymmetric, and whether either subunit can be involved in signaling remains unknown Such analysis will likely bring interesting observation for the understanding of the allosteric coupling between GPCRs within hetero-complexes. These data reveal strong allosteric interactions between two GPCRs in a dimeric complex Such allosteric coupling can be controlled with small molecules allosteric modulators revealing a way to modulate heteromeric receptor activity, and expanding the possibilities of using such small molecules to precisely control signaling events. This illustrates how such hetero-complexes can control signals originating from various GPCR ligands targeting a cell
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