{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRAMP2 is a critical accessory protein that partners with the calcitonin receptor‐like receptor (CLR) to form high‐affinity adrenomedullin (AM) receptors. Structural and biochemical studies have demonstrated that when CLR is coexpressed with RAMP2, the extracellular ligand‐binding pocket of the receptor is remodelled to preferentially bind AM. In addition, detailed crystallographic analyses reveal that RAMP2, by contributing unique contacts and inducing subtle CLR conformational changes, is essential for specifying AM receptor pharmacology. These observations underscore the functional role of RAMP2 in defining receptor ligand selectivity and in complementing the intrinsic properties of CLR in the formation of functional AM receptors."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to shaping ligand binding, RAMP2 plays a key role in the intracellular trafficking and signaling of G protein–coupled receptor complexes. Functional studies have shown that specific domains within RAMP2, including its cytoplasmic C‐tail, are necessary for efficient cell surface expression of CLR complexes and for mediating proper agonist‐evoked responses. Moreover, RAMP2 has been reported to interact with other GPCRs such as the glucagon receptor, altering both receptor distribution and G protein coupling preferences. Collectively, these data indicate that RAMP2 not only contributes to receptor pharmacology via extracellular domain interactions but also governs post‐endocytic receptor sorting and signaling pathway activation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond receptor formation and trafficking, the AM–RAMP2 signaling system exerts significant tissue‐specific protective effects. In the vascular and renal systems, RAMP2‐containing receptors mediate vasodilation, suppress endoplasmic reticulum stress–induced cell death, and modulate fibrosis. In the immune and pulmonary contexts, altered localization of RAMP2 and its receptor complex may influence thymic function and alveolar as well as vascular development. Furthermore, dysregulation of RAMP2 has been implicated in cardiovascular pathologies—including stroke and heart failure—and in inflammatory conditions such as rheumatoid arthritis, underscoring its importance in maintaining tissue homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent evidence also indicates that the regulation of RAMP2 expression itself can influence disease progression. In non‐small cell lung cancer, for example, a long noncoding RNA (RAMP2-AS1) has been shown to stabilize RAMP2 mRNA through interaction with specific RNA binding proteins, thus attenuating cancer cell proliferation and invasion. This emerging regulatory layer further highlights the importance of RAMP2 in both normal physiology and pathophysiology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"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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