NPR3 Gene: Natriuretic Peptide Receptor 3 - Function, Mutations, and Disease

NPR3 encodes the natriuretic peptide receptor 3 (NPR-C), a clearance receptor for atrial (ANP), brain (BNP), and C-type (CNP) natriuretic peptides. Unlike NPR1 and NPR2, NPR3 lacks guanylyl cyclase activity and primarily functions to internalize and degrade natriuretic peptides, thereby regulating their local and circulating concentrations. The receptor is widely expressed in vascular smooth muscle, endothelium, kidney, bone, and adipose tissue. NPR3 also mediates G-protein-coupled signaling independent of cGMP, influencing cell proliferation, fibrosis, and bone growth. Loss-of-function mutations in NPR3 are associated with bone overgrowth and blood pressure variation.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Natriuretic peptide signaling pathway (Reactome: R-HSA-418594)

• cGMP-PKG signaling pathway (KEGG: hsa04022)

• Regulation of blood pressure (KEGG: hsa04924)

• Bone remodeling (Reactome: R-HSA-8878166)

Natriuretic peptide receptor 3 (NPR-C) is a 540-amino acid transmembrane protein encoded by NPR3. It consists of a large extracellular ligand-binding domain, a single transmembrane helix, and a short intracellular tail lacking guanylyl cyclase activity. The receptor binds ANP, BNP, and CNP with high affinity and mediates their internalization and lysosomal degradation. NPR-C also couples to Gi/o proteins to inhibit adenylyl cyclase and activate phospholipase C, modulating cell proliferation and fibrosis. The protein is heavily N-glycosylated and forms homodimers. Its expression in bone, vasculature, and kidney underpins its roles in skeletal growth, blood pressure regulation, and fluid homeostasis.