Biomedical Engineering Reference
In-Depth Information
design novel treatments for neuropathic pain and to increase the effectiveness of
SSRIs (Pichon et al.
2010
) .
The importance of D
1
/D
2
heterodimers in human disease was suggested in a
recent study showing that physical interaction between dopamine D
1
and D
2
receptors
is markedly increased in postmortem brains of patients suffering from major depres-
sion. Administration of an interfering peptide consisting of a sequence located in
the third intracellular loop of D
2
that disrupts the D
1
-D
2
receptor complex reduced
immobility in the forced swim test without affecting locomotor activity, and
decreased escape failures in learned helplessness tests in rats (Pei et al.
2010
) . This
study thus provided evidence for potential implication of GPCR heterodimers and
associated signaling specificity in human diseases.
12.8
Conclusions
Evolution has selected several ways to achieve signaling specificity, by generating
receptor isoforms, receptor polymorphisms, differential localization and targeting
of receptors and pre-assembly of receptors and GAPCs into defined and distinct
signaling modules. The latter holds the potential to explain many of the observed
signaling specificity. However, we are only beginning to define the precise composi-
tion and impact of these modules on receptor signaling. Given the dynamic nature
of these modules, a precise analysis has to be performed for each receptor in a
specific cellular context and under defined physiological and pathological
conditions.
Acknowledgements
We thank Jean-Luc Guillaume (Institut Cochin, Paris) for critical reading of
the manuscript. This work was supported by grants from the Fondation pour la Recherche Médicale
(“Equipe FRM”, to RJ), Institut National de la Santé et de la Recherche Médicale (INSERM),
Centre National de la Recherche Scientifique (CNRS), Servier and a research fellowship from the
Ile-de-France region (ABC).
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