EDNRB (endothelin receptor type B) is a G protein-coupled receptor that mediates signaling by endothelins 1, 2, and 3 through phosphatidylinositol-calcium second messenger pathways. EDNRB plays critical roles in enteric nervous system development and pigmentation during neural crest cell differentiation 1. The receptor functions in multiple developmental and physiological processes. It regulates enteric neurogenesis, as demonstrated by studies showing GDNF-induced neuronal regeneration in EDNRB-deficient mouse models of Hirschsprung disease 2. EDNRB is expressed in specialized capillary endothelial cells (aerocytes) in the lung 3 and serves as a marker for iron-rich tumor-associated macrophages that support angiogenesis and immunosuppression 4. Additionally, EDN3/EDNRB signaling promotes browning of white adipose tissue through cAMP-EPAC1-ERK activation, regulating thermogenic differentiation and metabolic homeostasis 5. Clinically, EDNRB mutations cause Hirschsprung disease (characterized by intestinal aganglionosis) 6 and Waardenburg syndrome type IV (Shah-Waardenburg syndrome), featuring pigmentation abnormalities, hearing loss, and enteric nervous system dysfunction 7. EDNRB deficiency in Hirschsprung patients increases sensorineural deafness risk 8. Understanding EDNRB biology offers therapeutic potential for treating these congenital conditions and metabolic disorders.