{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nReceptor activity–modifying protein 3 (RAMP3) is a pivotal accessory subunit for a subset of family B G protein–coupled receptors. When coexpressed with the calcitonin receptor–like receptor (CLR), RAMP3 enables the formation of a high‐affinity adrenomedullin receptor (the AM2 receptor) that plays a critical role in vasodilation and the regulation of cerebral and systemic vascular tone. In addition, when associated with receptors such as the calcitonin receptor, RAMP3 helps to modulate ligand specificity toward peptides including calcitonin gene–related peptide (CGRP) and amylin, thereby diversifying receptor phenotypes and ensuring appropriate cell surface trafficking and signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, RAMP3 contains distinct structural determinants—most notably a PDZ type I motif in its intracellular C-terminal domain—that govern receptor trafficking and postendocytic sorting. Studies employing site-directed mutagenesis have revealed that specific residues (for example, those at position 74 in RAMP1/RAMP3 and certain extracellular histidine residues) are critical for mediating ligand potency and receptor signaling. In addition, alterations in the transmembrane and C-terminal regions affect receptor coupling to G proteins and the recycling of receptor complexes. These findings underscore the role of RAMP3 in directing the intracellular fate of receptors by engaging with partners such as NSF and NHERF-1, thereby fine-tuning receptor resensitization and internalization."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in receptor assembly and trafficking, RAMP3 is implicated in broader physiological and pathological contexts. For example, interactions between RAMP3 and other G protein–coupled receptors can rescue misfolded receptor mutants and modulate the balance of receptor populations, as demonstrated with the secretin receptor complex. In cancer models, upregulation of RAMP3 by factors such as LOXL2 promotes invasiveness and tumor progression, highlighting its potential as a therapeutic target. Moreover, altered RAMP3 expression has been correlated with prognostic outcomes in hepatocellular carcinoma and changes in mRNA levels have been observed in heart failure, while comparative studies in amphibians further support its functional conservation and tissue-specific roles."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kevin R Oliver, Anna Wainwright, Lars Edvinsson, et al. 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