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heterodimers or oligomers with peculiar pharmacological properties are spe-
cifically formed would constitute a unique target of great interest. So far,
only a few examples have been reported in the literature to illustrate this
concept, but the examples described below should stimulate the use of
new assays to screen for molecules exhibiting specific pharmacological prop-
erties on a dimer or oligomer.
4.2.3.1 Specific pharmacological properties of GPCR oligomers
First, using the fluorescent ligands mentioned above, Albizu and colleagues
were able to demonstrate an asymmetric relationship of the two protomers
in the oxytocin receptor dimers or oligomers in native mammary glands
(cooperative binding), confirming results obtained in cell lines.
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Second, adenosine A1 and A2A receptor were shown to heteromerize and
their heteromerization allows adenosine to exert a fine-tuning modulation of
glutamatergic transmission. Using radioligand binding, the authors showed the
unique pharmacological properties for this heteromer, and they also showed
that it is a unique target for caffeine and that chronic treatment leads to modifi-
cation in the function of this heteromer that could underlie the strong toler-
ance to the psychomotor effects of caffeine.
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A third example was reported in
a study using confocal microscopy and TR-FRET. Kern and colleagues
showed that subsets of native neurons in the hypothalamus (a structure impli-
cated in the regulation of appetite) naturally present heterodimers composed
of the dopamine receptor subtype-2 (D2R) and the ghrelin receptor
(GHSR1a).
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To that aim, they used, on one side, a ghrelin ligand fused to
a red acceptor fluorophore and, on the other side, a specific antibody for
D2R and a secondary antibody labeled with a TR-FRET-compatible donor.
This association allosterically modifies the coupling properties of the dimer as
compared to each receptor on its own, as well as desensitization mechanisms.
Even without ghrelin activation, GHSR1a could be an allosteric modulator of
dopamine-D2R signaling in response to endogenous dopamine, and thus it
would allow a neuronal selective fine tuning of dopamine/D2R signaling,
as neurons expressing D2R alone will be unaffected. This heteromerization
has important therapeutic implications because extensive resources have been
invested in developing GHSR1a antagonists as antiobesity agents, and poly-
morphisms in D2R impair D2R signaling and are associated with obesity in
humans.
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In this physiological context, the authors predicted that GHSR1a
antagonists might exacerbate rather than prevent obesity. This new mecha-
nism allowingmodulation of specific neurons by GHSR1a-D2Rheterodimer
formation offers exciting opportunities for designing the next generation of
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