The Functional Size of GPCRs – Monomers, Dimers or Tetramers? - GPCR Signalling Complexes: Synthesis, Assembly, Trafficking and Specificity - page 75

tagged with each half of split-Venus with the b 1 AR-Rluc or b 2 AR-Rluc in a hetero-
oligomeric context (Fig. 4.2b, c ). None of these interactions were sensitive to block
with dominant negative versions of either Rab1 (Fig. 4.2a, b , c) suggesting that like
receptor dimers, both homo- and hetero-oligomers also form in the ER as an early
event in receptor biogenesis.
The role of pre-assembly has important implications for the formation of
asymmetric, receptor-based signalling complexes. Asymmetry in the context of
GPCR heterodimers can be viewed in multiple ways - either structural, functional
or a combination of the two. Functional asymmetry can be defined as differences in
signalling mediated by a receptor heterodimer, where occupancy of one receptor
alters signalling via the other and this relationship may differ depending on how the
receptors are stimulated - that is the asymmetry need not necessarily be reciprocal.
To understand functional asymmetries, we first need to more extensively character-
ize signalling pathways downstream of putative heterodimers. Teasing out the
determinants of such assemblies will be critical for understanding what complexes
are formed in a given context and may provide mechanistic insight into how
asymmetric arrays are built. One simple way to use this system is to test the notion
that the timing of synthesis, or the order of assembly, of key signalling components
associated with a given GPCR heterodimer or hetero-oligomer determines which
receptor becomes the signalling receptor and which becomes the allosteric modula-
tor. We would argue that targeting assembly of signalling complexes might actually
provide an even more “selective” set of biased assembly modulators than current
approaches designed to find biased ligands. However, much work remains to iden-
tify the molecular determinants of signalling complex assembly in the interim.
Acknowledgments This work was supported by grants from the Canadian Institutes of Health
Research to T.E.H (MOP-36379) as well as the CIHR Team in GPCR Allosteric Regulation
(CTiGAR). T.E.H. is a Chercheur National of the Fonds de la Recherche en Santé du Québec
(FRSQ). We thank Vic Rebois (NIH) and the Hébert lab for helpful discussions.
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