GPRC5B is an orphan G protein-coupled receptor with emerging roles in cell volume regulation and inflammatory signaling. The protein is critically involved in astrocyte volume homeostasis, as de novo heterozygous variants in GPRC5B cause megalencephalic leukoencephalopathy with subcortical cysts (MLC), a genetic brain edema disorder 1. GPRC5B is expressed in astrocyte endfeet in human brain and functionally interacts with ion channels involved in volume regulation 1. Mechanistically, GPRC5B operates through protein-protein interactions with other GPCRs, particularly facilitating prostaglandin E receptor 2 (EP2) signaling in macrophages, which modulates anti-inflammatory responses 2. The receptor also regulates inflammatory and fibrotic pathways in cardiac fibroblasts, where its expression is induced by TNFα, LPS, and mechanical stretch, subsequently modulating production of inflammatory cytokines and extracellular matrix components 3. Additionally, GPRC5B promotes collagen production in myofibroblasts and is upregulated in fibrotic tissues 4. In the central nervous system, GPRC5B-deficient mice exhibit altered spontaneous activity and decreased response to new environments, indicating important roles in behavior control 5. These diverse functions establish GPRC5B as a potential therapeutic target for brain edema, inflammatory diseases, and fibrotic conditions.