RGS21 (regulator of G protein signaling 21) is a negative regulator of G protein-coupled receptor (GPCR) signaling that functions as a GTPase-activating protein (GAP). The protein contains a conserved RGS domain of ~120 amino acids that directly binds activated G protein alpha subunits and accelerates their intrinsic GTPase activity, driving them into inactive GDP-bound states and terminating downstream signals 1. At 152 amino acids, RGS21 represents the smallest known RGS family member without additional functional domains, likely belonging to the B/R4 subfamily with specificity for αi/o and αq/11 family members 1. RGS21 shows ubiquitous tissue expression 1 and is particularly notable in taste bud and airway epithelial cells, where it specifically inhibits bitter tastant signaling by opposing cAMP and calcium second messenger responses 2. Functionally, RGS21 acts as a GAP for multiple G protein alpha subunits implicated in tastant signal transduction 2. Clinically, RGS21 genetic variants associate with celiac disease susceptibility, with specific SNPs showing significant associations in genome-wide analyses 3. Additionally, RGS21 SNPs show potential associations with chr1 rhinosinusitis progression, though results were not statistically significant 4. These findings suggest RGS21's involvement in immune-related signaling pathways beyond taste perception.