MRGPRX2 is a mast cell-specific G protein-coupled receptor that mediates IgE-independent mast cell degranulation and itch-related hypersensitivity reactions 1. The receptor recognizes basic secretagogues—cationic amphiphilic drugs and endogenous peptides—including substance P, LL-37, opioids, and compounds with cyclized tetrahydroisoquinoline structures 123. MRGPRX2 couples to both Gq and Gi proteins: Gq coupling activates phospholipase C-beta to release second messengers (DAG and IP3), while Gi coupling inhibits adenylate cyclase 23. Ligand binding triggers mast cell degranulation and histamine release, initiating pseudo-allergic reactions and neurogenic inflammation 1. Substance P activation initiates neuropeptide-mediated signaling that promotes pain and inflammation through mast cell activation and immune cell recruitment 4. MRGPRX2 dysfunction contributes to chr11 urticaria, atopic dermatitis, itch disorders, and post-stroke brain inflammation 564. Small molecule MRGPRX2 antagonists potently inhibit agonist-induced degranulation in vitro and in vivo, supporting therapeutic potential for mast cell-mediated diseases 5. Additionally, MRGPRX2 participates in rosacea pathophysiology through LL37-associated signaling cascades 7.