Allostery at G Protein-Coupled Receptor Homo- and Heteromers: Uncharted Pharmacological Landscapes

Single-molecule analysis of fluorescently labeled G-protein–coupled receptors reveals complexes with distinct dynamics and organization

“…First, whereas the latter methods are associated with partial labeling and/or possible influences of negative cooperativity in ligand binding (38,39), virtually complete receptor labeling can be achieved. Second, our approach allows us to analyze ligand-free receptors and to study the effects of agonists or antagonists.…”

Heteromeric Dopamine Receptor Signaling Complexes: Emerging Neurobiology and Disease Relevance

“…The modification of the signaling properties by receptor oligomerization may constitute another manifestation of the effects of allosterism, whether these changes are minor resulting in differences in efficacy or are major with a complete signal switching (reviewed in Smith and Milligan, 2010), as is the case for the D1-D2 heteromer. The stimulation of the dopamine D1-D2 receptor heteromer, for instance, triggers a Gq-mediated intracellular mobilization of calcium that neither D1R or D2R individually are associated with, and whose specificity was shown using D1R À / À , D2R À / À , and D5R À / À gene-deleted mice (George and O'Dowd, 2007;Rashid et al, 2007a, Hasbi et al, 2009.…”

“…In many cases, receptor heteromerization has been shown to confer novel pharmacological profiles as well as signaling properties different from those of the protomers that constitute these receptor complexes (George and O'Dowd, 2007;Maggio et al, 2009;Smith and Milligan, 2010). Interestingly, these receptor heteromer complexes are mostly confined to some brain regions, as is the case for the dopamine D1-D2 heteromer (Hasbi et al, 2009;Perreault et al, 2010), which makes targeting GPCR heteromers a pharmacological alternative that offers the advantage of a higher brain region specificity and a better targeting of receptor signals.…”

“…Receptor oligomerization through protein-protein interactions can be considered as a form of allosterism (Maggio et al, 2009), in that the binding of a compound to one protomer of the heteromer may positively or negatively modulate the drug occupancy of the other protomer, or in some cases, some heteromers may display a selectivity to ligands not observed in the case of individual receptors (George and O'Dowd, 2007;Maggio et al, 2009;Smith and Milligan, 2010). In the first type of scenario, some examples were cited for the GABAB receptor complex (Galvez et al, 2001), for A2-D2 receptor heterodimers (Franco et al, 2000), D2-D3 heteromers (Maggio et al, 2009), delta-kappa opioid heterodimers (Jordan and Devi, 1999), as well as for somatostatin-dopamine sSST5-D2 receptors (Rocheville et al, 2000) (reviewed in Maggio et al, 2009).…”

Métaphores, nomenclature et nouveaux paradigmes de signalisation par les récepteurs couplés aux protéines G

“…Cette dimension plurielle de l'efficacité de signalisation des RCPG offre toutefois de nouvelles opportunités pour le développement de médi-caments plus efficaces et ayant moins d'effets indésirables, en ciblant sélectivement les voies de signalisations importantes pour leur action thérapeutique. La constatation que, contrairement à ce qui était générale-ment admis, les RCPG ne sont pas que des protéines monomé-riques, mais peuvent former des dimères, voire des oligomères de plus grande taille, offre aussi de nouvelles perspectives pour le développement de thérapies innovantes [9,10]. En particulier, l'existence d'hétérodimères formés de sous-types de récepteurs distincts, qui acquièrent des propriétés pharmacologiques et de signalisation différentes de celles de chacun des protomères, ouvre la porte au développement de composés qui ciblent sélectivement certains hétérodimères pour des indications cliniques précises.…”