Functional Homomers and Heteromers of Dopamine D2L and D3 Receptors Co-exist at the Cell Surface

Pou, Chantévy; Cour, Clotilde Mannoury la; Stoddart, Leigh A.; Millan, Mark J.; Milligan, Graeme

doi:10.1074/jbc.m111.326678

Cited by 41 publications

(35 citation statements)

References 60 publications

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“…More recently, the D2-D3 heteromer was demonstrated to coexist with D2R and D3R homomers in cells at the plasma membrane using the newly developed SNAP and CLIP tag reagents (Pou et al, 2012). A putative role for the D2-D3 heteromer as a target for antipsychotics and, in particular, for antipsychotics with partial D2R agonism has been suggested (Maggio and Millan, 2010), an idea based on findings in cells that in the presence of excess D3R, the properties of partial D2R agonists, such as the antipsychotic aripiprazole, were transformed to antagonist actions (Novi et al, 2007).…”

Section: The Dopamine D1-d3 D2-d3 and D2-d5 Receptor Heteromersmentioning

confidence: 99%

Heteromeric Dopamine Receptor Signaling Complexes: Emerging Neurobiology and Disease Relevance

Perreault

Hasbi

O’Dowd

et al. 2013

Neuropsychopharmacol

143

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: The Dopamine D1-d3 D2-d3 and D2-d5 Receptor Heteromersmentioning

confidence: 99%

Heteromeric Dopamine Receptor Signaling Complexes: Emerging Neurobiology and Disease Relevance

Perreault

Hasbi

O’Dowd

et al. 2013

Neuropsychopharmacol

143

107

View full text Add to dashboard Cite

show abstract

“…It will be interesting to discover if other heteromers between dopamine receptor subtypes also are stabilized by interactions involving elements of the intracellular loops. Other heteromers between dopamine receptor subtypes have, indeed, been reported, including D 1 -D 3 (Marcellino et al, 2008;Ferre et al, 2010;Moreno et al, 2011a), D 2 -D 3 (Pou et al, 2012), and D 2 -D 4 (González et al, 2012) complexes, but the basis for their interactions and potential functional sequelae have not yet been explored in the level of detail of the D 1 -D 2 heteromer. Interestingly, although it is widely accepted that the detection of receptor heteromers is likely to be associated with the concurrent presence of the corresponding homomers, this is difficult to assess in ex vivo situations, and even in vitro this has only recently been explored in cells coexpressing varying amounts of the dopamine D 2 and D 3 receptors to show that the expectation of a mixture of homomers and heteromers was likely to be correct (Pou et al, 2012).…”

Section: Gpcr Quaternary Structure: Relevance Tomentioning

confidence: 99%

The Prevalence, Maintenance, and Relevance of G Protein–Coupled Receptor Oligomerization

2013

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Over the past decade, ideas and experimental support for the hypothesis that G protein-coupled receptors may exist as dimeric or oligomeric complexes moved initially from heresy to orthodoxy, to the current situation in which the capacity of such receptors to interact is generally accepted but the prevalence, maintenance, and relevance of such interactions to both pharmacology and function remain unclear. A vast body of data obtained following transfection of cultured cells is still to be translated to native systems and, even where this has been attempted, results often remain controversial and contradictory. This review will consider approaches that are currently being applied and why these might be challenging to interpret, and will suggest means to overcome these limitations.

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“…To the extent that co-occupancy of D2Rs and D3Rs is required to attenuate cocaine reinforcement, such interactions may occur in the same or different neurons or may involve D2R-D3R heterodimers (Maggio et al, 2003;Pou et al, 2012). In vivo positron emission tomography imaging using D2R-and D3R-selective imaging agents may aid the development of compounds with "threshold" D3R:D2R occupancy levels that can attenuate low response-demand cocaine self-administration while minimizing side effects Tu et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Reduction of Cocaine Self-Administration and D3 Receptor-Mediated Behavior by Two Novel Dopamine D3 Receptor-Selective Partial Agonists, OS-3-106 and WW-III-55

Cheung¹,

Loriaux²,

Weber³

et al. 2013

J Pharmacol Exp Ther

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Dopamine D3 receptor (D3R)-selective compounds may be useful medications for cocaine dependence. In this study, we identified two novel arylamide phenylpiperazines, OS-3-106 and WW-III-55, as partial agonists at the D3R in the adenylyl cyclase inhibition assay. OS-3-106 and WW-III-55 have 115-and 862-fold D3R:D2 receptor (D2R) binding selectivity, respectively. We investigated their effects (0, 3, 5.6, or 10 mg/kg) on operant responding by using a multiple variable-interval (VI) 60-second schedule that alternated components with sucrose reinforcement and components with intravenous cocaine reinforcement (0.375 mg/kg). Additionally, we evaluated the effect of OS-3-106 (10 mg/kg) on the dose-response function of cocaine selfadministration and the effect of WW-III-55 (0-5.6 mg/kg) on a progressive ratio schedule with either cocaine or sucrose reinforcement. Both compounds were also examined for effects on locomotion and yawning induced by a D3R agonist. OS-3-106 decreased cocaine and sucrose reinforcement rates, increased latency to first response for cocaine but not sucrose, and downshifted the cocaine self-administration dose-response function. WW-III-55 did not affect cocaine self-administration on the multiple-variable interval schedule, but it reduced cocaine and sucrose intake on the progressive ratio schedule. Both compounds reduced locomotion at doses that reduced responding, and both compounds attenuated yawning induced by low doses of 7-OH-DPAT (a D3R-mediated behavior), but neither affected yawning on the descending limb of the 7-OH-DPAT dose-response function (a D2R-mediated behavior). Therefore, both compounds blocked a D3R-mediated behavior. However, OS-3-106 was more effective in reducing cocaine selfadministration. These findings support D3Rs, and possibly D2Rs, as targets for medications aimed at reducing the motivation to seek cocaine.

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Functional Homomers and Heteromers of Dopamine D2L and D3 Receptors Co-exist at the Cell Surface

Cited by 41 publications

References 60 publications

Heteromeric Dopamine Receptor Signaling Complexes: Emerging Neurobiology and Disease Relevance

Heteromeric Dopamine Receptor Signaling Complexes: Emerging Neurobiology and Disease Relevance

The Prevalence, Maintenance, and Relevance of G Protein–Coupled Receptor Oligomerization

Reduction of Cocaine Self-Administration and D3 Receptor-Mediated Behavior by Two Novel Dopamine D3 Receptor-Selective Partial Agonists, OS-3-106 and WW-III-55

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