Heterodimerization of dopamine receptors: new insights into functional and therapeutic significance

Maggio, Roberto; Aloisi, Gabriella; Silvano, Elena; Rossi, Mario; Millan, Mark J.

doi:10.1016/s1353-8020(09)70826-0

Cited by 59 publications

(43 citation statements)

References 57 publications

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“…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.…”

Section: Bivalent Ligandsmentioning

confidence: 99%

“…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).…”

Section: Allosterismmentioning

confidence: 99%

Section: Allosterismmentioning

confidence: 99%

“…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). For the second case, which relates to the differing specificity of certain ligands to either the heteromer or a constituent homomer, some examples were described such as for the dopamine D1-D2 heteromer (Rashid et al, 2007b) and dopamine D2-D3 heteromer (Maggio and Millan, 2010;Maggio et al, 2009). For example, two D1R-like agonists, SKF 83959 and SKF 83822, although showing high radioligand-binding affinities for the D1R in D1-D2 or D1-D1 receptor complexes, showed very specific functional effects, with SKF 83959 robustly stimulating the D1-D2 heteromer-mediated calcium signal and not activating adenylyl cyclase by the D1-D1 homomer, whereas SKF 83822 robustly stimulated adenylyl cyclase by the D1-D1 homomer with no effect on calcium release through the D1-D2 heteromer complexes (George and O'Dowd, 2007;Rashid et al, 2007a;Hasbi et al, 2009).…”

Section: Allosterismmentioning

confidence: 99%

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Heteromeric Dopamine Receptor Signaling Complexes: Emerging Neurobiology and Disease Relevance

Perreault

Hasbi

O’Dowd

et al. 2013

Neuropsychopharmacol

138

107

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The pharmacological modification of dopamine transmission has long been employed as a therapeutic tool in the treatment of many mental health disorders. However, as many of the pharmacotherapies today are not without significant side effects, or they alleviate only a particular subset of symptoms, the identification of novel therapeutic targets is imperative. In light of these challenges, the recognition that dopamine receptors can form heteromers has significantly expanded the range of physiologically relevant signaling complexes as well as potential drug targets. Furthermore, as the physiology and disease relevance of these receptor heteromers is further understood, their ability to exhibit pharmacological and functional properties distinct from their constituent receptors, or modulate the function of endogenous homomeric receptor complexes, may allow for the development of alternate therapeutic strategies and provide new avenues for drug design. In this review, we describe the emerging neurobiology of the known dopamine receptor heteromers, their physiological relevance in brain, and discuss the potential role of these receptor complexes in neuropsychiatric disease. We highlight their value as targets for future drug development and discuss innovative research strategies designed to selectively target these dopamine receptor heteromers in the search for novel and clinically efficacious pharmacotherapies.

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Section: Bivalent Ligandsmentioning

confidence: 99%

Section: Allosterismmentioning

confidence: 99%

Section: Allosterismmentioning

confidence: 99%

Section: Allosterismmentioning

confidence: 99%

See 2 more Smart Citations

Heteromeric Dopamine Receptor Signaling Complexes: Emerging Neurobiology and Disease Relevance

Perreault

Hasbi

O’Dowd

et al. 2013

Neuropsychopharmacol

138

107

View full text Add to dashboard Cite

show abstract

“…Dopaminergic signaling is not entirely based on the cAMP pathway. DA binds to multiple receptors that can stimulate several G proteins [25,26] and thus, activate intracellular pathways different from those activated by dbcAMP alone [22,27]. The current study investigates whether DA treatment can improve the yield and quality of hESC-derived DA neurons.…”

Section: Introductionmentioning

confidence: 99%

Dopamine Receptors in Human Embryonic Stem Cell Neurodifferentiation

Belinsky

Sirois

Rich

et al. 2013

Stem Cells and Development

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We tested whether dopaminergic drugs can improve the protocol for in vitro differentiation of H9 human embryonic stem cells (hESCs) into dopaminergic neurons. The expression of 5 dopamine (DA) receptor subtypes (mRNA and protein) was analyzed at each protocol stage (1, undifferentiated hESCs; 2, embryoid bodies [EBs]; 3, neuroepithelial rosettes; 4, expanding neuroepithelium; and 5, differentiating neurons) and compared to human fetal brain (gestational week 17-19). D2-like DA receptors (D2, D3, and D4) predominate over the D1-like receptors (D1 and D5) during derivation of neurons from hESCs. D1 was the receptor subtype with the lowest representation in each protocol stage (Stages 1-5). D1/D5-agonist SKF38393 and D2/D3/D4-agonist quinpirole (either alone or combined) evoked Ca 2 + responses, indicating functional receptors in hESCs. To identify when receptor activation causes a striking effect on hESC neurodifferentiation, and what ligands and endpoints are most interesting, we varied the timing, duration, and drug in the culture media. Dopaminergic agonists or antagonists were administered either early (Stages 1-3) or late (Stages 4-5). Early DA exposure resulted in more neuroepithelial colonies, more neuronal clusters, and more TH + clusters. The D1/D5 antagonist SKF83566 had a strong effect on EB morphology and the expression of midbrain markers. Late exposure to DA resulted in a modest increase in TH + neuron clusters (*75%). The increase caused by DA did not occur in the presence of dibutyryl cAMP (dbcAMP), suggesting that DA acts through the cAMP pathway. However, a D2-antagonist (L741) decreased TH + cluster counts. Electrophysiological parameters of the postmitotic neurons were not significantly affected by late DA treatment (Stages 4-5). The mRNA of mature neurons (VGLUT1 and GAD1) and the midbrain markers (GIRK2, LMX1A, and MSX1) were lower in hESCs treated by DA or a D2-antagonist. When hESCs were neurodifferentiated on PA6 stromal cells, DA also increased expression of tyrosine hydroxylase. Although these results are consistent with DA's role in potentiating DA neurodifferentiation, dopaminergic treatments are generally less efficient than dbcAMP alone.

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Design Strategies for Bivalent Ligands Targeting GPCRs

Shonberg¹,

Scammells²,

Capuano³

2011

ChemMedChem

127

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Specifically designed bivalent ligands targeting G protein-coupled receptor (GPCR) dimeric structures have become increasingly popular in recent literature. The advantages of the bivalent approach are numerous, including enhanced potency and receptor subtype specificity. However, the use of bivalent ligands as potential pharmacotherapeutics is limited by problematic molecular properties, such as high molecular weight and lipophilicity. This minireview focuses on the design of bivalent ligands recently described in the literature; discussing the choice of lead pharmacophore, the position and nature of the attachment point for linking the two pharmacophore units, and the length and composition of the spacer group. Furthermore, this minireview distils the molecular descriptors of the bivalent ligands that exhibit in vivo activity, as well as highlights their ability to access the central nervous system.

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Heterodimerization of dopamine receptors: new insights into functional and therapeutic significance

Cited by 59 publications

References 57 publications

Heteromeric Dopamine Receptor Signaling Complexes: Emerging Neurobiology and Disease Relevance

Heteromeric Dopamine Receptor Signaling Complexes: Emerging Neurobiology and Disease Relevance

Dopamine Receptors in Human Embryonic Stem Cell Neurodifferentiation

Design Strategies for Bivalent Ligands Targeting GPCRs

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