Design, synthesis and biological evaluation of bivalent ligands against A1–D1 receptor heteromers

Shen, Jian; Zhang, Lei; Song, Wanling; Meng, Tao; Wang, Xin; Chen, Lin; Feng, Linyin; Xu, Yechun; Shen, Jingkang

doi:10.1038/aps.2012.151

Cited by 19 publications

(17 citation statements)

References 30 publications

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“…Thus, the stimulation of the mGlu 5 receptor potentiates A 2A signalling in a MAPK-dependent manner in striatal slices [43] and could be mediated by the formation of A 2A /mGlu 5 /D 2 receptor heteromers [119]. An interesting possibility is the simultaneous activation of two different GPCRs, when heteromerized, through bivalent ligands, as has previously been evaluated in the case of A 1 /D 1 [120], A 2A /D 2 [121] or μ opioid receptor/mGlu 5 [122] heteromers.…”

Section: New Drug Design Possibilities: Targeting Gpcr Oligomersmentioning

confidence: 99%

Functional Cross-Talk between Adenosine and Metabotropic Glutamate Receptors

León-Navarro

Albasanz

Martı́n

2019

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G-protein coupled receptors are transmembrane proteins widely expressed in cells and their transduction pathways are mediated by controlling second messenger levels through different G-protein interactions. Many of these receptors have been described as involved in the physiopathology of neurodegenerative diseases and even considered as potential targets for the design of novel therapeutic strategies. Endogenous and synthetic allosteric and orthosteric selective ligands are able to modulate GPCRs at both gene and protein expression levels and can also modify their physiological function. GPCRs that coexist in the same cells can homo- and heteromerize therefore modulating their function. Adenosine receptors are GPCRs which stimulate or inhibit adenylyl cyclase activity through Gi/Gs protein and are involved in the control of neurotransmitter release as glutamate. In turn, metabotropic glutamate receptors are also GPCRs which inhibit adenylyl cyclase or stimulate phospholipase C activities through Gi or Gq proteins respectively. In recent years evidence of crosstalk mechanisms between different GPCRs have been described. The aim of the present review was to summarize the described mechanisms of interaction and crosstalking between adenosine and metabotropic glutamate receptors, mainly of group I, in both in vitro and in vivo systems, and their possible use for the design of novel ligands for the treatment of neurodegenerative diseases.

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Section: New Drug Design Possibilities: Targeting Gpcr Oligomersmentioning

confidence: 99%

Functional Cross-Talk between Adenosine and Metabotropic Glutamate Receptors

León-Navarro

Albasanz

Martı́n

2019

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“…The ability of GPCRs, in general, and of the dopamine receptors, in particular, to oligomerize is well established (47)(48)(49)(50)(51)(52)(53)(54)(55)(56). These complexes may be composed of identical protomers or monomers (aka homomers) or of different protomers (aka heteromers).…”

Section: Discussionmentioning

confidence: 99%

Tandem Requirement for Full Renal D₁R and D₅R Activity

Rozyyev

Crusan

Tiu

et al. 2019

Preprint

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The peripheral dopaminergic system promotes the maintenance of blood pressure homeostasis by engendering natriuresis, mainly through the renal D 1 R and D 5 R receptors. This effect is most apparent under conditions of moderate body sodium excess. Human and rodent renal proximal tubules express both receptors, which share common structural features and pharmacological profiles. Genetic ablation of either receptor in the kidney results in hypertension in mice. In this study, we demonstrated that in renal proximal tubules, these two receptors colocalized, co-immunoprecipitated, co-segregated in lipid rafts, and heterodimerized with one another, which was enhanced by treatment with the D 1 R/D 5 R agonist fenoldopam (1 M, 30 min). Gene silencing via antisense oligonucleotides in renal proximal tubule cells abrogated cAMP production and sodium transport in response to fenoldopam. Our results highlight the cooperation and co-dependence of these two receptors through heterodimerization in renal proximal tubule cells. ABBREVIATIONSBiFC (Bimolecular fluorescence complementation), cAMP (cyclic adenosine monophosphate), D 1 R (dopamine D1 recpetor), D 5 R (dopamine D5 receptor) EYFP (enhanced yellow fluorescent protein) HEK293 (Human embryonic kidney) cells, hRPTCs (human renal proximal tubule cells), GPCR (G protein-coupled receptor), sodium-potassium pump (Na + /K + -ATPase), and sodium-hydrogen exchanger 3 (NHE3)

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“…A 1 and D 1 receptors, separately, also tend to form homodimers; however, the preferred form of dimerization for these two receptors still needs to be elucidated ( Agnati et al, 2003 ). Additionally, A 1 /D 1 dimerization was also confirmed by FRET in HEK-293T cells ( Shen et al, 2013 ).…”

Section: Hetero-dimers Between Adenosine (A 1 and mentioning

confidence: 91%

Receptor–Receptor Interactions of G Protein-Coupled Receptors in the Carotid Body: A Working Hypothesis

et al. 2018

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In the carotid body (CB), a wide series of neurotransmitters and neuromodulators have been identified. They are mainly produced and released by type I cells and act on many different ionotropic and metabotropic receptors located in afferent nerve fibers, type I and II cells. Most metabotropic receptors are G protein-coupled receptors (GPCRs). In other transfected or native cells, GPCRs have been demonstrated to establish physical receptor–receptor interactions (RRIs) with formation of homo/hetero-complexes (dimers or receptor mosaics) in a dynamic monomer/oligomer equilibrium. RRIs modulate ligand binding, signaling, and internalization of GPCR protomers and they are considered of relevance for physiology, pharmacology, and pathology of the nervous system. We hypothesize that RRI may also occur in the different structural elements of the CB (type I cells, type II cells, and afferent fibers), with potential implications in chemoreception, neuromodulation, and tissue plasticity. This ‘working hypothesis’ is supported by literature data reporting the contemporary expression, in type I cells, type II cells, or afferent terminals, of GPCRs which are able to physically interact with each other to form homo/hetero-complexes. Functional data about cross-talks in the CB between different neurotransmitters/neuromodulators also support the hypothesis. On the basis of the above findings, the most significant homo/hetero-complexes which could be postulated in the CB include receptors for dopamine, adenosine, ATP, opioids, histamine, serotonin, endothelin, galanin, GABA, cannabinoids, angiotensin, neurotensin, and melatonin. From a methodological point of view, future studies should demonstrate the colocalization in close proximity (less than 10 nm) of the above receptors, through biophysical (i.e., bioluminescence/fluorescence resonance energy transfer, protein-fragment complementation assay, total internal reflection fluorescence microscopy, fluorescence correlation spectroscopy and photoactivated localization microscopy, X-ray crystallography) or biochemical (co-immunoprecipitation, in situ proximity ligation assay) methods. Moreover, functional approaches will be able to show if ligand binding to one receptor produces changes in the biochemical characteristics (ligand recognition, decoding, and trafficking processes) of the other(s). Plasticity aspects would be also of interest, as development and environmental stimuli (chronic continuous or intermittent hypoxia) produce changes in the expression of certain receptors which could potentially invest the dynamic monomer/oligomer equilibrium of homo/hetero-complexes and the correlated functional implications.

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Design, synthesis and biological evaluation of bivalent ligands against A1–D1 receptor heteromers

Cited by 19 publications

References 30 publications

Functional Cross-Talk between Adenosine and Metabotropic Glutamate Receptors

Functional Cross-Talk between Adenosine and Metabotropic Glutamate Receptors

Tandem Requirement for Full Renal D₁R and D₅R Activity

Receptor–Receptor Interactions of G Protein-Coupled Receptors in the Carotid Body: A Working Hypothesis

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Design, synthesis and biological evaluation of bivalent ligands against A1–D1 receptor heteromers

Cited by 19 publications

References 30 publications

Functional Cross-Talk between Adenosine and Metabotropic Glutamate Receptors

Functional Cross-Talk between Adenosine and Metabotropic Glutamate Receptors

Tandem Requirement for Full Renal D1R and D5R Activity

Receptor–Receptor Interactions of G Protein-Coupled Receptors in the Carotid Body: A Working Hypothesis

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Tandem Requirement for Full Renal D₁R and D₅R Activity