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4.2.1.2 Effect of oligomerization on GPCR activation and pharmacology
Besides modulating GPCR cell-surface expression, oligomerization is also a
key factor for modifying the binding properties of the ligands and G protein
coupling properties and thus the activated signaling pathways, opening a
new level of complexity in the GPCR pharmacological properties.
First, GPCR heteromerization can generate specific binding properties
either by modulating ligand binding through allostery or by promoting
new binding pockets. For instance, CCR5 was shown to associate with an-
other member of the chemokine receptor family, CCR2, resulting in a
heterodimer capable of binding only a single chemokine molecule, and this
was interpreted as negative binding cooperativity.
60
In the opioid receptor
family, 6-guanidinonaltrindole (6-GNTI), an opioid agonist ligand used as
an analgesic, was shown to preferentially activate heterodimers of
k
-opioid
(KOP) and
d
opioid (DOP) receptors over the homomeric counterparts.
61
This example illustrates the possibility of finding ligands selective for a
specific heterodimer. It means that, if the organization of heterodimers is
tissue specific or even neuron specific in the central nervous system, consid-
ering that not all cells express the same repertoire of GPCRs, it should be
possible to use heterodimer-selective ligands to target only the appropriate
heterodimer in the appropriate cells, thus reducing adverse effects from ac-
tivation of homomeric counterparts from the same cells or from other cells.
Second, heteromerization can induce a shift in the G protein family
activated by the complex compared to individual components. Very strong
evidence for a major role of heterodimers in key functional events in the
cells is found in the dopaminergic receptor family. D1R and D2R have
been shown to form heterodimers that could play a role in patients
suffering from major depression, as their expression is increased in post-
mortembrainofsuchpatients.
62
Their heteromerization leads to a switch
from a G
a
s/olf (D1-like classical response) or G
a
i (D2-like response) to a
G
a
q/11-mediated response,
63
and the compound SKF83959, previously
known as a D1R agonist, is able to bind the D1-D2 heteromer and
activate this specific Gq pathway in the brain. Moreover, D2R has also
been shown to form heteromers with D5R, resulting in modified
pharmacological properties when compared to activation of each proto-
mer on its own.
64
Third, GPCR heteromerization can induce a shift from a G protein-
dependent pathway to aGprotein-independent pathway. The heteromerization
of the chemokine receptors CXCR4 and CXCR7 leads to a strong biased
agonism, as
it promotes
the constitutive recruitment of
b
-arrestin and
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