The Heteromeric Dopamine Receptor D2:D3 Controls the Gut Recruitment and Suppressive Activity of Regulatory T-Cells
Abstract
1. Introduction
2. Results
2.1. Drd2-Mediated Signalling Favours the Suppressive Activity of Treg and Limits Gut Inflammation
2.2. Drd2-Mediated Signalling Promotes Colonic Tropism of Treg upon Gut Inflammation
2.3. IBD Patients Display Increased DRD3 and Reduced DRD2 Expression in Mucosal Lesions
2.4. Drd2 and Drd3 Form a Heteromeric Complex on Colonic Treg Cells
2.5. The Drd2:Drd3 Heteromer Controls the Suppressive Activity and Colonic Tropism of Treg
3. Discussion
4. Materials and Methods
4.1. Animals
4.2. Reagents
4.3. Dextran Sodium Sulphate Induced Acute Inflammatory Colitis
4.4. Histological Analysis
4.5. In Vitro Suppression Assay
4.6. In Vivo Migration Assay
4.7. In Vitro Migration Assay
4.8. Flow Cytometry Analysis
4.9. Bulk RNA-Seq Analysis
4.10. Bioluminescence Resonance Energy Transfer Assay
4.11. Bimolecular Fluorescence Complementation Assay
4.12. In Situ Proximity Ligation Assay
4.13. cAMP Levels Determination
4.14. Determination of ERK1/2 Phosphorylation
4.15. Determination of AKT Phosphorylation
4.16. Statistical Analyses and Sample Size Estimation
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AnR | adenosine receptor An |
BiFC | bimolecular fluorescence complementation |
BRET | bioluminescence resonance energy transfer |
BSA | bovine serum albumin |
CD | Crohn’s disease |
CCR9 | chemokine receptor 9 |
cLP | colonic lamina propria |
CTV | cell trace violet |
DCs | dendritic cells |
DSS | dextran sodium sulfate |
Drdn | dopamine receptor n |
GFP | green fluorescent protein |
GPCR | G-protein coupled receptor |
IBD | inflammatory bowel disease |
IL-n | interleukin n |
Teff | effector T-cells |
MadCAM-1 | mucosal vascular addressing Cell Adhesion Molecule 1 |
MLNs | mesenteric lymph nodes |
MNCs | mononuclear cells |
PLA | proximity ligation assay |
PPs | Peyer’s patches |
RLuc | renilla luciferase |
PMA | phorbol 12-myristate 13-acetate |
TAT | transactivator of transcription |
Thn | T-helper n |
Treg | regulatory T-cells |
TMs | transmembrane segments |
UC | ulcerative colitis |
WT | wild-type |
YFP | yellow fluorescent protein |
ZAq | Zombie Aqua |
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Functional Name | Short Name | Sequence 1 |
---|---|---|
TM1hDRD2-TAT | TM1Drd2 | ATLLTLLIAVIVFGNVLVSMAVSYGRKKRRQRRR |
TAT-TM2hDRD2 | TM2Drd2 | RRRQRRKKRGYYLIVSLAVADLLVATLVMPWVVY |
TM3hDRD2-TAT | TM3Drd2 | IFVTLDVMMSTASILNLSAISIYGRKKRRQRRR |
TAT-TM4hDRD2 | TM4Drd2 | RRRQRRKKRGYVTVMISIVWVLSFTISSPLLF |
TM5hDRD2-TAT | TM5Drd2 | FVVYSSIVSFYVPFIVTLLVYIKIYYGRKKRRQRRR |
TAT-TM6hDRD2 | TM6Drd2 | RRRQRRKKRGYMLAIVLGVFIISWLPFFITHIL |
TM7hDRD2-TAT | TM7Drd2 | AFTWLGYVNSAVNPIIYTTFNIYGRKKRRQRRR |
TM1hDRD3-TAT | TM1Drd3 | ALSYSALILAIVFGNGLVSMAVLYGRKKRRQRRR |
TAT-TM2hDRD3 | TM2Drd3 | RRRQRRKKRGYYLVVSLAVADLLVATLVMPWVVY |
TM3hDRD3-TAT | TM3Drd3 | VFVTLDVMMSTASILNLSAISIYGRKKRRQRRR |
TAT-TM4hDRD3 | TM4Drd3 | RRRQRRKKRGYVALMITAVWVLAFAVSSPLLF |
TM5hDRD3-TAT | TM5Drd3 | FVIYSSVVSFYLPFGVTVLVYARIYYGRKKRRQRRR |
TAT-TM6hDRD3 | TM6Drd3 | RRRQRRKKRGYMVAIVLGAFIVSWLPFFLTHVL |
TM7hDRD3-TAT | TM7Drd3 | ATTWLGYVNSALNPVIYTTFNIYGRKKRRQRRR |
Feature | Score | Description |
---|---|---|
Inflammation | 0 | None |
1 | Slight | |
2 | Moderate | |
3 | Severe | |
Extent of injury | 0 | None |
1 | Mucosal | |
2 | Mucosal and sub-mucosal | |
3 | Transmural | |
Crypt damage | 0 | None |
1 | Basal 1/2 damage | |
2 | Basal 2/3 damage | |
3 | Only surface epithelium intact | |
4 | Entire crypt and epithelium lost | |
The score of each parameter above is multiplied by a factor reflecting the percentage of tissue involved as indicated below | ||
Percentage involved | Factor | |
0–25% | 1 | |
26–50% | 2 | |
51–75% | 3 | |
76–100% | 4 |
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Mora, J.; Raïch, I.; Ugalde, V.; Navarro, G.; Prado, C.; Vidal, P.M.; Leal, P.; Espinoza, A.; Liu, M.; Weersma, R.; et al. The Heteromeric Dopamine Receptor D2:D3 Controls the Gut Recruitment and Suppressive Activity of Regulatory T-Cells. Int. J. Mol. Sci. 2025, 26, 10069. https://doi.org/10.3390/ijms262010069
Mora J, Raïch I, Ugalde V, Navarro G, Prado C, Vidal PM, Leal P, Espinoza A, Liu M, Weersma R, et al. The Heteromeric Dopamine Receptor D2:D3 Controls the Gut Recruitment and Suppressive Activity of Regulatory T-Cells. International Journal of Molecular Sciences. 2025; 26(20):10069. https://doi.org/10.3390/ijms262010069
Chicago/Turabian StyleMora, Jacob, Iu Raïch, Valentina Ugalde, Gemma Navarro, Carolina Prado, Pia M. Vidal, Pedro Leal, Alexandra Espinoza, Moting Liu, Rinse Weersma, and et al. 2025. "The Heteromeric Dopamine Receptor D2:D3 Controls the Gut Recruitment and Suppressive Activity of Regulatory T-Cells" International Journal of Molecular Sciences 26, no. 20: 10069. https://doi.org/10.3390/ijms262010069
APA StyleMora, J., Raïch, I., Ugalde, V., Navarro, G., Prado, C., Vidal, P. M., Leal, P., Espinoza, A., Liu, M., Weersma, R., Gacesa, R., Hermoso, M. A., Franco, R., & Pacheco, R. (2025). The Heteromeric Dopamine Receptor D2:D3 Controls the Gut Recruitment and Suppressive Activity of Regulatory T-Cells. International Journal of Molecular Sciences, 26(20), 10069. https://doi.org/10.3390/ijms262010069