The Functional Size of GPCRs – Monomers, Dimers or Tetramers? - GPCR Signalling Complexes: Synthesis, Assembly, Trafficking and Specificity - page 71

b ; Carriba et al. 2008 ; Gandia et al. 2008 ) and CXCR4 multimers (Hamatake et al.
2009 ) can be detected.
Different FRET approaches have also indicated similar higher order structures
for the M2 muscarinic receptor and the b 2 AR (Pisterzi et al. 2010 ; Fung et al. 2009 ) .
The former study provides additional structural details regarding these complexes
that impact on the potential asymmetry of GPCR signalling complex organization.
Using spectral de-convolution and fluorescence lifetime imaging, these authors
were also able to show that M2 receptor homotetramers are likely to be in a rhom-
boid orientation, rather than a simple square array of receptor monomers ((Pisterzi
et al. 2010 ) , Fig. 4.1 ). Receptors that signal as monomers will not have the allosteric
possibilities for modulation inherent in receptor dimers or higher order structures
(Fig. 4.1a ). Further, homodimers or even homotetramers in a square array, have
fewer possibilities for asymmetric arrangements compared to rhomboid-shaped
homotetramers, where structural asymmetries can be introduced with respect to
how the entire receptor, G protein, effector complex is arranged (Fig. 4.1b ). In a
heterodimer, there is already an inherent component of asymmetry (Fig. 4.1c ).
Based on a study from the Javitch group (Han et al. 2009 ), this adds an entirely
unappreciated wrinkle to signalling from heterodimers. They showed that the two-
receptor equivalents in the context of a D2 dopamine receptor homodimer are orga-
nized asymmetrically with respect to their G protein partners (Han et al. 2009 ) such
that occupation by ligand of one receptor activates the receptor and occupation of
the other modulates signalling allosterically. In the context of a homodimer this may
not be so important as either receptor can serve each role and the asymmetry may
not be detectable. However, in hetero-oligomers, structural asymmetries in
receptor/G protein assembly may have dramatic consequences for signalling.
One obvious functional advantage of dimers, more easily understood in the con-
text of heterodimers, is that they can act on each other via allosteric interactions,
which may or may not depend on ligand occupation. In fact, a recent study suggested
that ghrelin receptor significantly alters D2 dopamine receptor signalling, via hetero-
dimerization in brain regions which never see ghrelin, suggesting a function for the
apo-receptor as a pure allosteric modulator, rather than as a signalling receptor in
these cells (Kern et al. 2012 ). Similar findings were obtained with D1/D2 dopamine
receptor dimers (Rashid et al. 2007 ). We have recently demonstrated that a hetero-
dimer forms between the b 2 AR and the oxytocin receptor (Wrzal et al. 2012a, b ) .
We showed that the b 2 AR/OTR is an allosteric dimer pair in myometrial cells
expressing both receptors endogenously. Specifically, occupation of the b 2 AR binding
Fig. 4.1 (continued) and in how this information is transmitted to interacting proteins. ( d ) Assembly
of asymmetric GPCR heterodimers which interact in distinct ways with a shared G protein can be
assembled in different orientations such that in one case, R1 signals and R2 is a non-signalling
allosteric modulator (whether occupied by ligand or not) of R1. The converse arrangement is also
possible. Receptor homodimers might be asymmetrically organized with respect to their G protein
and effector partners but this is unlikely to have functional consequences per se since cooperative
effects between the receptor equivalents could be sensed in the same way