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simultaneous impairment of the usual CXCR4 Gi-mediated signaling.
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In the
opioid receptor family, under normal physiological conditions, the
m
-opioid
receptor (MOP) is foundmostly as homo-oligomers in the brain, and its traffick-
ing is regulated by oligomerization.
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Upon acute morphine stimulation, the G
protein-mediated signaling pathway is activated and leads to analgesic effects.
However, upon chronic morphine administration, the abundance of MOP-
DOP heteromers is increased in key areas of the central nervous system which
are implicated in pain processing, and they could impair the analgesic effects of
morphine by recruiting
b
-arrestin and thus alteringMOP homomer signaling.
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4.2.1.3 GPCR oligomers: New targets for HTS campaigns
Despite all these striking examples of the importance of oligomerization in
GPCR functioning, and despite the fact that dimerization is a common phe-
nomenon for other membrane proteins, only little thought has been given
for a long time to the importance of quaternary structure in HTS campaigns
and the priority was to design highly specific and selective ligands on one
target protein. However, this was due to the lack of HTS-compatible
methods to take into account the role of oligomerization in modulating
pharmacological responses. Nowadays, new methods, and especially some
based on TR-FRET, are emerging to allow first the identification of GPCR
homo- or heteromers and then to study whether the association modifies the
pharmacological and functional properties of the oligomer. Thus, it may be
possible to screen compounds that will specifically target one GPCR
heteromer and maybe achieve specific therapeutic potential with reduced
adverse effects. So far, only a few homo- or heteromers examples have been
validated for their potential as new therapeutic targets, and more will prob-
ably be needed before they become common targets for HTS screening.
However, the development of specific HTS assays dedicated to study these
complexes will help to stimulate screening campaigns in this direction.
4.2.2 TR-FRET screening for homo-/heteromer formation
The critical point before studying a peculiar GPCR complex and its func-
tional properties is, of course, to be able to identify it, ideally in a native en-
vironment. And when such a homo- or heteromer is identified, all the
generic methods mentioned above can be used to investigate its particular
properties. However, another important point to consider is whether the
modulation of this complex assembly can also modulate its properties. If this
is the case, one can imagine screening for ligands favoring or disturbing the
interactions. For example, drugs preventing the dissociation of transthyretin
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