Atrial natriuretic peptide receptor 3 (NPR-C) (NPR-C)

Atrial natriuretic peptide receptor 3 (NPR-C) is a single-pass transmembrane protein that serves as the primary clearance receptor for the natriuretic peptide family, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) (UniProt, 2024). By binding and internalizing these peptides for lysosomal degradation, NPR-C tightly regulates their systemic and local concentrations, thereby modulating their vasodilatory, diuretic, and metabolic effects (PubMed, 2005). Although historically viewed as a silent receptor due to its lack of an intracellular guanylyl cyclase domain, NPR-C is now recognized to possess independent signaling capabilities through coupling with inhibitory G proteins (Gi), which leads to the inhibition of adenylyl cyclase and activation of phospholipase C (PubMed, 2005; Frontiers, 2021). It also acts as a decoy receptor for osteocrin, influencing bone growth and skeletal development (UniProt, 2024). In disease states, NPR-C is implicated in the pathogenesis of heart failure, hypertension, and obesity, where its expression levels can significantly impact cardiovascular and metabolic homeostasis (Circulation, 2013). Pharmacological modulation of NPR-C, either through selective agonists like cANF(4-23) or inhibitors like M372049, represents a promising therapeutic avenue for managing conditions such as heart failure with preserved ejection fraction (HFpEF) and chronic kidney disease (Frontiers, 2021; Nature, 2024).

Other names

NPR3ANP-CANPR-CANPRCGCA-RGUCY2BC5orf23BOMOSAtrial natriuretic peptide clearance receptorAtrial natriuretic peptide receptor type C

NPR-C primarily functions as a clearance receptor that binds, internalizes, and degrades natriuretic peptides (ANP, BNP, and CNP) via receptor-mediated endocytosis, thereby regulating their circulating levels (UniProt, 2024). It also acts as a signaling receptor by coupling to inhibitory G proteins (Gi), which leads to the inhibition of adenylyl cyclase and the activation of phospholipase C (PubMed, 2005). Additionally, NPR-C can form nonfunctional heterodimers with NPR-A and NPR-B, directly suppressing their guanylyl cyclase activity and subsequent cGMP production (PNAS, 2023).