Movatterモバイル変換

[0]ホーム
URL:

Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
Thehttps:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

NIH NLM Logo
Log inShow account info
Access keysNCBI HomepageMyNCBI HomepageMain ContentMain Navigation
pubmed logo
Advanced Clipboard
User Guide

Full text links

Elsevier Science full text link Elsevier Science Free PMC article
Full text links

Actions

Share

Comparative Study
.2011 Sep;61(4):770-7.
doi: 10.1016/j.neuropharm.2011.05.023. Epub 2011 May 27.

Functional crosstalk and heteromerization of serotonin 5-HT2A and dopamine D2 receptors

Affiliations
Comparative Study

Functional crosstalk and heteromerization of serotonin 5-HT2A and dopamine D2 receptors

Laura Albizu et al. Neuropharmacology.2011 Sep.

Abstract

The serotonin 5-HT(2A) receptor (5-HT(2A)R) and dopamine D(2) receptor (D(2)R) are high-affinity G protein-coupled receptor targets for two different classes of antipsychotic drugs used to treat schizophrenia. Interestingly, the antipsychotic effects are not based on the regulation of same signaling mediators since activation of the 5-HT(2A)R and of the D(2)R regulate G(q/11) protein and G(i/o) protein, respectively. Here we use radioligand binding and second messenger production assays to provide evidence for a functional crosstalk between 5-HT(2A)R and D(2)R in brain and in HEK293 cells. D(2)R activation increases the hallucinogenic agonist affinity for 5-HT(2A)R and decreases the 5-HT(2A)R induced inositol phosphate production. In vivo, 5-HT(2A)R expression is necessary for the full effects of D(2)R antagonist on MK-801-induced locomotor activity. Co-immunoprecipitation studies show that the two receptors can physically interact in HEK293 cells and raise the possibility that a receptor heterocomplex mediates the crosstalk observed. The existence of this 5-HT(2A)R-D(2)R heteromer and crosstalk may have implications for diseases involving alterations of serotonin and dopamine systems and for the development of new classes of therapeutic drugs.

Copyright © 2011. Published by Elsevier Ltd.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
5-HT2AR radioligand competitive curves performed in HEK293 cells and mouse striatum.A, In HEK293 cells co-expressing 5-HT2AR and D2R, 5-HT2AR agonist DOI affinity is higher in the presence of D2R agonist quinpirole (10−5 M) (two-site model;Ki-high = 1.1 × 10−11 M andKi-low = 2.8 × 10−8 M) (○) from the control (one-site model;Ki = 1.7 × 10−8 M) (■).B, In HEK293 cells expressing only 5-HT2AR, DOI affinity does not change in the presence of quinpirole (10−5 M) (two-site model;Ki-high = 2.9 × 10−10 M,Ki-low = 3.5 × 10−8 M) (○) from the control (two-site model;Ki-high = 5.8 × 10−10 M,Ki-low = 4.2 × 10−8 M) (■).C, In mouse striatum, DOI affinity is significantly higher in the presence of quinpirole (10−5 M) (two-site model;Ki-high = 1.5 × 10−11 M andKi-low = 4.7 × 10−7 M) (○) from the control (one-site model;Ki = 9.5 × 10−8 M) (■).D, In mouse striatum, the increased DOI affinity in the presence of quinpirole (10−5 M) (two-site model;Ki-high = 8.5 × 10−11 M andKi-low = 6.9 × 10−8 M) (○) from the control (one-site model;Ki = 3.3 × 10−6 M) (■) is decreased when D2R antagonist raclopride is added (one-site model;Ki = 2.7 × 10−7 M) (●). Data are means ± SEM for each experiment performed in triplicate. TheKi values shown are for this single experiment. Averages ofKi values are indicated in Table 1.
Fig. 2
Fig. 2
Inositol Phosphate (IP) production induced by 5-HT2AR activation with natural agonist 5-HT or hallucinogenic drug DOI. A, Serotonin (5-HT)-stimulated 5-HT2AR in HEK293 cells expressing 5-HT2AR (△) and HEK293 cells co-expressing 5-HT2AR and D2R (■). D2R expression does not affect 5-HT-induced 5-HT2AR-IP3 production (EC50 = 5.5 × 10−7 M).B, DOI-stimulated 5-HT2AR in HEK293 cells expressing 5-HT2AR (△) (EC50 = 3.8 × 10−6 M) and HEK293 cells co-expressing 5-HT2AR and D2R (■) (EC50 = 6.7 × 10−8 M). D2R expression increases DOI-induced 5-HT2AR-IP3 production.C, D2R agonists (10−5 M), quinpirole (○) (EC50 = 6.6 × 10−7 M) and ropinirole (◇) (EC50 = 8 × 10−7 M), have no effect on 5-HT-induced 5-HT2AR-IP3 production (vehicle; EC50 = 5.5 × 10−7 M).D, D2R agonists (10−5 M), quinpirole (○) (EC50 = 3.9 × 10−7 M) and ropinirole (◇) (EC50 = 2.4 × 10−7 M) decrease DOI-induced 5-HT2AR-IP3 production (vehicle; EC50 = 6.7 × 10−8 M). Data are means ± SEM for each experiment performed in triplicate. The EC50 values shown are for this single experiment. Averages of EC50 values over all experiments can be found in Table 2.
Fig. 3
Fig. 3
5-HT2AR is necessary to induce D2R ligand dependent behavioral effects in mice. Expression of 5-HT2AR is necessary for the inhibition of MK-801-induced locomotor activity by D2R antagonist haloperidol.A, The time course of MK-801-induced locomotion is measured in 5 min blocks. Time of injections of MK-801 is indicated by arrows. Horizontal activity is measured in wild-type (WT) and 5-HT2AR-KO mice.B, Corresponding bar graph of the total MK-801-induced locomotion as a summation of horizontal activity fromt = 10 min tot = 120 min. Mice were administered haloperidol (1 mg/kg) or vehicle followed by MK-801 (0.5 mg/kg; i.p.) (n = 6; **p < 0.01; error bars shows SEM).
Fig. 4
Fig. 4
5-HT2AR and D2R co-immunoprecipitate.A, Specific co-immunoprecipitation of 5-HT2AR and D2R in HEK293 cells. RLuc-tagged D2R and GFP-tagged 5-HT2AR were immunoprecipitated using anti-GFP or RLuc antibodies. Membranes were probed with either anti-RLuc antibody or anti-N-Cadherin antibody. The co-immunoprecipitated receptor complex is indicated by the box in the upper right panel.B, RLuc-tagged D2R and GFP-tagged 5-HT2AR, mGluR2 or mGluR3 were immunoprecipitated using anti-RLuc antibody and membranes were probed with anti-GFP antibody. A co-immunoprecipitated receptor is detected only for D2R with 5-HT2AR.C, RLuc-tagged D2R and GFP-tagged D2R, 5-HT2AR, mGluR2 or mGluR3 were immunoprecipitated using anti-GFP antibody and membranes were probed with anti-RLuc antibody. Complex formation was observed only for D2R homomers and D2R-5-HT2AR heteromers. Panels are representative of three independent experiments. WB, western blot. IP, immunoprecipitation.
Fig. 5
Fig. 5
5-HT2AR-D2R heteromer crosstalk hypothesis: effects of D2R expression and activation on 5-HT2AR binding and signaling properties. On the left, serotonin 5-HT2AR is illustrated as binding its agonist DOI and being coupled to Gq/11 protein. In the middle, dopamine D2R expression might have an allosteric effect (illustrated with a white arrow) on 5-HT2AR by decreasing DOI agonist affinity to 5-HT2AR and increasing 5-HT2AR coupling to Gq/11 protein. In contrast, on the right, D2R activation (induced by its agonist quinpirole) leads to an increased affinity of 5-HT2AR for DOI and a decreased Gq/11 protein coupling to 5-HT2AR.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Adayev T, Ranasinghe B, Banerjee P. Transmembrane signaling in the brain by serotonin, a key regulator of physiology and emotion. Biosci Rep. 2005;25:363–385. - PubMed
    1. Albizu L, Balestre MN, Breton C, Pin JP, Manning M, Mouillac B, et al. Probing the existence of G protein-coupled receptor dimers by positive and negative ligand-dependent cooperative binding. Mol Pharmacol. 2006;70:1783–1791. - PubMed
    1. Albizu L, Teppaz G, Seyer R, Bazin H, Ansanay H, Manning M, et al. Toward efficient drug screening by homogeneous assays based on the development of new fluorescent vasopressin and oxytocin receptor ligands. J Med Chem. 2007;50:4976–4985. - PubMed
    1. Albizu L, Cottet M, Kralikova M, Stoev S, Seyer R, Brabet I, et al. Time-resolved FRET between GPCR ligands reveals oligomers in native tissues. Nat Chem Biol. 2010a;6:587–594. - PMC - PubMed
    1. Albizu L, Moreno JL, Gonzalez-Maeso J, Sealfon SC. Heteromerization of G protein-coupled receptors: relevance to neurological disorders and neuro-therapeutics. CNS Neurol Disord Drug Targets. 2010b;9:636–650. - PMC - PubMed

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full text links
Elsevier Science full text link Elsevier Science Free PMC article
Cite
Send To

NCBI Literature Resources

MeSHPMCBookshelfDisclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

[8]ページ先頭
©2009-2025 Movatter.jp