The Heteromeric Dopamine Receptor D2:D3 Controls the Gut Recruitment and Suppressive Activity of Regulatory T-Cells
Year: 2025
Type: article
Abstract: Since colonic dopamine levels undergo a sharp reduction in inflammatory bowel disease (IBD) and animal models, we study how dopaminergic signalling affects regulatory T cells (Treg), which are critical limiting gut inflammation. Previously, we showed that the stimulation of the high-affinity dopamine receptor Drd3 impairs the suppressive Treg ac-tivity and limits their colonic tropism upon gut inflammation. Here we study the role of the low-affinity dopamine receptor Drd2 in Treg, finding that stimulation of Drd2 favours the suppressive Treg activity and promotes their colonic tropism. Transcriptomic analysis of intestinal mucosa from IBD patients revealed an association with increased DRD3 and reduced DRD2 expression. Biochemical approaches revealed that Drd2 and Drd3 form a heteromeric receptor. Competition assays using α-helix peptides analogue to the trans-membrane (TM) segments from Drd2 and Drd3 showed that TM5 from Drd2 (TM5Drd2) and TM2Drd3 and TM6Drd3 disrupt the assembly of this heteromer. The Drd2:Drd3 het-eromer was expressed on colonic Treg, and its expression was increased upon inflamma-tion. The heteromer disassembly dampened the suppressive Treg activity and impaired their colonic tropism upon inflammation. Our findings indicate that the Drd2:Drd3 het-eromer constitutes a dopamine sensor that plays a critical role on the suppressive Treg ac-tivity and colonic tropism.
Institutions: San Sebastián University, Fundación Ciencia and Vida, Universitat de Barcelona, Fundación Arturo López Pérez, Instituto de Salud Carlos III, Biomedical Research Networking Center on Neurodegenerative Diseases, Universidad Católica de la Santísima Concepción, University Medical Center Groningen, University of Chile
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,499
Awards: G1128043559, ROLE OF MICROBIOTA IN THE TRAFFICKING OF INTESTINAL IMMUNE CELLS INTO THE CNS IN HOMEOSTASIS AND DISEASE, DECIPHERING THE ROLE OF THE HETEROMERIC COMPLEX FORMED BY DOPAMINE RECEPTORS D2 AND D3 IN THE CONTROL OF REGULATORY T CELL FUNCTION IN THE GUT MUCOSA, G757605202, DECIPHERING THE ROLE OF THE SHORT-CHAIN FATTY ACIDS RECEPTOR GPR43 IN THE INTERPLAY BETWEEN T-CELLS AND THE MICROBIOTA IN THE DEVELOPMENT OF MOTOR AND NON-MOTOR MANIFESTATIONS IN PARKINSON'S DISEASE, CENTRO CIENTIFICO TECNOLOGICO DE EXCELENCIA CIENCIA & VIDA (CIENCIA & VIDA)
OpenAlex ID: W4415244991