Biology Reference
In-Depth Information
Given the recent excitement about allosteric modulation of GPCRs, we will focus
our discussion here and further on allosteric interactions in the context of GPCR di-
mers. Allosteric modulation within a receptor homodimer was elegantly demon-
strated for the class A dopamine D
2
receptor (D
2
R) (
Han, Moreira, Urizar,
Weinstein, & Javitch, 2009
). In that study, the authors used different combinations
of free receptor and receptor/G protein fusions to demonstrate these allosteric inter-
actions. Importantly, it was shown that one protomer actually provided a transacti-
vating signal to the fused G protein of the other protomer when the former was
occupied by an agonist. Agonist occupation of the second protomer actually damp-
ened signaling, likely through a mechanism involving negative cooperativity which
had previously been demonstrated using hormone desorption experiments in other
GPCRs (
Guan et al., 2009, 2010; Urizar et al., 2005
). Interestingly, as for the class
C mGluR (
Hlavackova et al., 2005
), binding of an agonist to the first protomer of the
dimer in conjunction with inverse agonist binding to the second protomer leads to the
highest efficacy (
Han et al., 2009
). Perhaps most intriguingly, this study showed that,
as in Class C GPCRs, class A homodimers may be arranged in an asymmetrical fash-
ion with respect to the G protein. These findings need to be reexamined in the context
of GPCR heterodimers as they have potentially important implications.
The assembly of asymmetric heterodimers or heterooligomers implies that allo-
steric machines may be constructed in a cell that respond to a single ligand in terms of
signaling output but could be allosterically regulated by ligands binding to different
heterodimer partners. If receptor/G protein complexes are in fact preassembled, prior
to reaching the plasma membrane (reviewed in
Dupr´ &H´bert, 2006; Dupr´,
Robitaille, Rebois, & H´bert, 2009
), then different orientations of these machines
might be constructed by reversing the specific asymmetric arrangement described
above. Thus, two distinct, allosterically regulated receptors that respond as a single
signaling unit, despite being a receptor heterodimer, may be regulated in distinct and
cell-specific ways depending on how they are arranged with respect to each other.
Thus, the formation of heterodimers could also lead to the formation of new signaling
pathways, as demonstrated with D
1
R/D
2
R heterodimeric receptor complex. When
expressed individually, these receptors do not couple to G
a
q. However, when coex-
pressed, they were able to stimulate this pathway (
Lee et al., 2004; Rashid et al.,
2007
). Taken together, these findings reveal the capacity of individual protomers
to interpret and bias signals delivered to GPCRs and transmit it into the cell in a myr-
iad of new ways. These notions will need to be accommodated in screens for biased
and allosteric ligands in future.
It is likely that the dimer is the minimal unit of GPCR organization and that olig-
omers exist for most receptors. As shown in
Fig. 9.1
C and D, each GPCR protomer of a
dimer is able tomodulate its own conformation, when bound and when interacting with
the other protomer of the complex. Each ligand might induce a specific conformation
responsible for functional selectivity of signaling observed downstream. Several re-
ports now discuss the notion of “receptor mosaics” that would each have specific func-
tions and could be allosterically regulated by a number of unique signaling partners
resident in any particular mosaic. Emerging imaging techniques such as resonance
