MrgD Receptor Modulates Neurotransmission in the Nigrostriatal Pathway

The Mas-related G protein-coupled receptor D (MrgD) is primarily known for its role in peripheral nociception and, more recently, as a receptor for alamandine, influencing cardiovascular function and exhibiting antidepressant-like effects. However, its function within the central nervous system, particularly in motor and reward-related circuits, remains largely unexplored. Here, we investigate the role of MrgD in the nigrostriatal pathway using proteomic approaches focused on post-translational modifications in MrgD-knockout (KO) mice. Integrated proteomic, phosphoproteomic, and N-glycoproteomic analyses revealed significant alterations in synaptic vesicle-associated proteins, pointing to impaired neurotransmission in the nigrostriatal system of KO mice. These molecular findings were supported by neurotransmitter quantification and functional assays demonstrating impaired synaptic vesicle exocytosis. Pharmacodynamic analyses showed that MrgD modulates synaptic exocytosis in an agonist-selective manner, being responsive to alamandine but not β-alanine. Furthermore, behavioral analyses revealed increased locomotor activity and compulsive-like behavior in MrgD-deficient mice, without impairments in short- or long-term memory. Together, these findings uncover a new role for MrgD beyond its involvement in nociception in central nervous system, highlighting this receptor as a potential therapeutic target for neurological disorders involving motor hyperactivity and compulsivity.