{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNPR3 encodes the natriuretic peptide receptor type C (NPR‐C), a unique single–pass transmembrane receptor that lacks intrinsic guanylyl cyclase activity and primarily functions as a clearance receptor for the cardiac natriuretic peptides (ANP, BNP, and CNP). Structural studies have revealed that NPR‐C adopts a bilobal periplasmic binding protein fold, enabling it to bind diverse, flexible natriuretic peptide ligands via a rigid, preformed binding surface; ligand binding induces large conformational changes in the membrane–proximal regions that are thought to initiate its clearance functions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " In addition, NPR3 is subject to dynamic regulation at the transcriptional and post–transcriptional levels; for example, its expression can be modulated by extracellular signals such as angiotensin II—which destabilizes its mRNA—and by microRNAs like miR–100 that fine–tune NPR3 levels in cardiac cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Furthermore, local binding of extracellular partners such as osteocrin to NPR3 can inhibit its clearance function, thereby elevating local natriuretic peptide bioavailability and influencing tissue processes like growth plate chondrocyte proliferation and bone elongation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic association studies have implicated NPR3 in human growth, blood pressure regulation, and cardiovascular disease. Variants in or near NPR3 are associated with adult stature as well as with hypertension, coronary artery disease, and ischemic stroke, suggesting that altered NPR3–mediated clearance of natriuretic peptides can influence vascular smooth muscle cell function, endothelial homeostasis, and downstream myocardial structure. Functional investigations in vascular tissues have demonstrated that lower NPR3 expression is linked to exaggerated angiotensin II–induced calcium flux, increased cell contraction, and enhanced proliferative responses, all of which contribute to increased blood pressure and the development of atherosclerotic lesions. Moreover, NPR3 also appears to modulate autonomic cardiac control, since experimental deletion of NPR3 leads to reduced heart rate variability and an imbalance in sympatho–vagal activity. The collective genetic and mechanistic data, including evidence from Mendelian randomization studies, support a central role for NPR3 and the natriuretic peptide clearance pathway in maintaining cardiovascular homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond the cardiovascular system, NPR3 plays important roles in diverse tissues and disease contexts. In the endocrine pancreas, NPR3 is selectively expressed in glucagon–producing α–cells and its activation promotes glucagon secretion, implicating it in metabolic regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": " It is also present in the ocular lens epithelium, where it may regulate local natriuretic peptide concentrations."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": " In cancer biology, NPR3 has been shown to exert tumor–suppressive effects; for instance, in hepatocellular carcinoma, upregulation of NPR3 (mediated via long noncoding RNA interactions) promotes apoptosis and cell cycle arrest, while in osteosarcoma, re–expression of NPR3 inhibits cell viability and tumor growth by blocking PI3K/AKT signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "29"}]}, {"type": "t", "text": " Moreover, NPR3 is implicated in the regulation of mesenchymal stem cell fate, contributing to osteogenic differentiation—a process that is finely balanced with adipogenesis—and in the developing lung, oxygen tension and steroid exposure modulate NPR3 expression in alveolar epithelial type II cells to influence surfactant secretion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}, {"type": "fg_f", "ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "F van den Akker "}, {"type": "b", "children": [{"type": "t", "text": "Structural insights into the ligand binding domains of membrane bound guanylyl cyclases and natriuretic peptide receptors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Biol (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1006/jmbi.2001.4922"}], "href": "https://doi.org/10.1006/jmbi.2001.4922"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11556325"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11556325"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Madhu B Anand-Srivastava "}, {"type": "b", "children": [{"type": "t", "text": "Natriuretic peptide receptor-C signaling and regulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Peptides (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.peptides.2004.09.023"}], "href": "https://doi.org/10.1016/j.peptides.2004.09.023"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15911072"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15911072"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Xiao-lin He, Abhiram Dukkipati, K Christopher Garcia "}, {"type": "b", "children": [{"type": "t", "text": "Structural determinants of natriuretic peptide receptor specificity and degeneracy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Biol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jmb.2006.06.060"}], "href": "https://doi.org/10.1016/j.jmb.2006.06.060"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16870210"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16870210"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yuhang Jiao, Qing Yang "}, {"type": "b", "children": [{"type": "t", "text": "Downregulation of natriuretic peptide clearance receptor mRNA in vascular smooth muscle cells by angiotensin II."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Fundam Clin Pharmacol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/fcp.12111"}], "href": "https://doi.org/10.1111/fcp.12111"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25711724"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25711724"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Lee Lee Wong, Abby S Y Wee, Jia Yuen Lim, et al. 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