{"gene":"RAMP1","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1999,"finding":"RAMP1 acts as a determinant of ligand specificity for the calcitonin receptor-like receptor (CRLR): coexpression of RAMP1 with CRLR generates a functional CGRP receptor (Gs-coupled), whereas RAMP2 coexpression yields an adrenomedullin receptor. RAMP1 competitively inhibits RAMP2-evoked ADM receptor expression, shifting receptor pharmacology to CGRP selectivity.","method":"Radioligand binding ([125I]hαCGRP, [125I]rADM), cAMP-responsive luciferase reporter assay, transient transfection in COS-7 and UMR-106 cells","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 1 — functional reconstitution with radioligand binding and cAMP assays, replicated across two cell lines","pmids":["10342881"],"is_preprint":false},{"year":2001,"finding":"RAMP1 expressed alone is retained intracellularly in the ER and Golgi as a disulfide-linked homodimer. Upon coexpression with CRLR, RAMP1 forms a 1:1 heterodimer that traffics to the cell surface; heterodimer formation promotes intramolecular disulfide bonds within RAMP1 but does not involve intermolecular disulfide bonds between the two partners. CGRP stimulation leads to CRLR phosphorylation and dynamin- and β-arrestin-dependent internalization of the CRLR–RAMP1 complex as a stable ternary complex with β-arrestin via clathrin-coated pits.","method":"Subcellular fractionation, non-reducing SDS-PAGE, co-immunoprecipitation, dominant-negative dynamin and β-arrestin constructs, confocal immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (biochemistry, dominant-negative genetics, imaging) in a single study with rigorous controls","pmids":["11535606"],"is_preprint":false},{"year":2007,"finding":"BRET titration experiments in living cells demonstrated that CRLR and RAMP1 selectively form heterodimers; both proteins can also independently form homodimers. RAMP1 is required for CRLR to engage G proteins and β-arrestin upon CGRP stimulation—CRLR alone cannot recruit these signaling partners.","method":"Bioluminescence resonance energy transfer (BRET) with Rluc/GFP fusion proteins, radioligand binding, cAMP production assay","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — live-cell BRET with titration experiments and functional validation by radioligand binding and cAMP assays","pmids":["17503773"],"is_preprint":false},{"year":2006,"finding":"Ab initio structural modeling of the RAMP1 extracellular domain determined the disulfide bond arrangement (Cys27–Cys82, Cys40–Cys72, Cys57–Cys104) by site-directed mutagenesis, and identified three α-helices (residues 29–51, 60–80, 87–100). The model predicted Phe93, Tyr100, Phe101 as a CLR-binding interface and Trp74, Phe92 as ligand-interaction residues.","method":"Site-directed mutagenesis of cysteines, ab initio structure prediction with molecular dynamics refinement, functional expression in COS-7 cells","journal":"Biophysical journal","confidence":"Medium","confidence_rationale":"Tier 1 for mutagenesis; Tier 4 for structural model — single lab, mutagenesis validated disulfide bonds but full structure is computational","pmids":["16632510"],"is_preprint":false},{"year":2009,"finding":"Alanine mutagenesis across the RAMP1 N-terminal extracellular domain identified Y66 and H97 as critical for CLR trafficking (receptor association), while L69, T73, and residues in helix 3 (P85, N86, F101) contribute to CGRP recognition and cAMP signaling. M48 had a modest effect on CLR surface delivery.","method":"Alanine-scanning mutagenesis of 22 RAMP1 residues, cell-surface ELISA, cAMP assay in Cos7 cells","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — systematic mutagenesis with functional readouts (trafficking and cAMP) across multiple residues","pmids":["19072332"],"is_preprint":false},{"year":2009,"finding":"Non-peptide CGRP receptor antagonists BIBN4096BS (olcegepant) and MK-0974 (telcagepant) interact with the CLR–RAMP1 interface: Trp-74 of RAMP1 is a key contact for both antagonists (W74K mutation reduces BIBN4096BS affinity >300-fold and MK-0974 affinity similarly), and Met-42 of CLR N-terminal domain is critical (M42A reduces BIBN4096BS affinity 48-fold, MK-0974 ~900-fold).","method":"Site-directed mutagenesis of CLR (residues 23–63) and RAMP1 (W74K), radioligand binding and functional assays","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis of both receptor components with quantitative affinity measurements for two clinical antagonists","pmids":["19914210"],"is_preprint":false},{"year":2010,"finding":"RAMP1 Trp-84 is critical for high-affinity binding of both non-peptide antagonists (telcagepant, olcegepant) and the peptide agonists CGRP and CGRP(8-37); Arg-67 of RAMP1 is selectively important for telcagepant but not the BIBN4096BS analog, indicating distinct but overlapping binding modes within the RAMP1 extracellular domain.","method":"Alanine replacement mutagenesis of RAMP1 residues, radioligand binding, functional cAMP assay in Cos7 cells","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 — systematic mutagenesis with binding and functional assays, confirms and extends prior structural data","pmids":["20188075"],"is_preprint":false},{"year":2010,"finding":"RAMP1–RAMP3 chimera analysis showed that helix 1 of RAMP1 and residues 62–69 of helix 2 are required for CLR trafficking (association), while residues 86–89 of RAMP1 helix 3 contribute to peptide (αCGRP, adrenomedullin) potency without affecting βCGRP, and residues 90–94 have dual roles in CLR recognition and CGRP binding.","method":"RAMP1–RAMP3 chimera construction, CLR trafficking assay (cell-surface ELISA), agonist-stimulated cAMP assay in Cos7 cells","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — chimeric protein analysis with trafficking and functional readouts across 26 constructs","pmids":["20017504"],"is_preprint":false},{"year":2011,"finding":"Position 74 of RAMP1 (Trp74) governs differential peptide pharmacology: substitutions alter AM potency at the CGRP receptor (CLR/RAMP1) differently from RAMP3 position 74 (Glu74), confirming this position as a determinant of ligand discrimination between adrenomedullin and CGRP at their respective receptors.","method":"Site-directed mutagenesis of position 74 in RAMP1 and RAMP3 with multiple amino acid substitutions, cAMP assay in Cos7 cells, cell-surface ELISA","journal":"Peptides","confidence":"Medium","confidence_rationale":"Tier 1 — mutagenesis with functional assays; single lab study","pmids":["21402116"],"is_preprint":false},{"year":2013,"finding":"RAMP1 overexpression in MG-63 osteoblast-like cells increases CRLR surface expression and enhances CGRP-induced osteogenic differentiation (alkaline phosphatase activity, collagen I expression, mineralization), demonstrating RAMP1's role in promoting CRLR membrane localization and amplifying CGRP-mediated osteoblast differentiation.","method":"Stable transfection with RAMP1 eukaryotic expression vector, RT-PCR, Western blot, immunofluorescence, ALP activity assay, Alizarin Red staining","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — gain-of-function with multiple differentiation readouts; single lab","pmids":["22949393"],"is_preprint":false},{"year":2013,"finding":"NKX3.1 transcription factor directly represses RAMP1 gene expression in prostate cells; RAMP1 knockdown reduces prostate cancer cell proliferation and tumorigenicity in vitro and in vivo, and decreases MEK1 expression and ERK1/2 phosphorylation, placing RAMP1 upstream of the MAPK signaling pathway in prostate cancer.","method":"ChIP-seq (NKX3.1 binding to RAMP1 locus), shRNA knockdown, gene expression profiling, xenograft tumor models, Western blot for pERK1/2","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 — ChIP-seq plus loss-of-function with in vivo validation and pathway analysis","pmids":["23867798"],"is_preprint":false},{"year":2014,"finding":"RAMP1-deficient mice show reduced airway resistance and airway inflammation in an ovalbumin-sensitized asthma model; loss of CLR from smooth muscle cells did not affect airway resistance, indicating CGRP signaling through RAMP1/CLR promotes asthma pathology via endothelial and inflammatory cells rather than smooth muscle.","method":"RAMP1 knockout mouse (exon 3 deletion), cell-specific CLR knockout, methacholine challenge, airway resistance measurement, histological assessment of inflammation","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function with cell-type-specific epistasis, defined physiological phenotype","pmids":["25010197"],"is_preprint":false},{"year":2018,"finding":"Photoaffinity cross-linking using unnatural amino acid (p-azido-L-phenylalanine) incorporated into CLR ECL2 identified key contacts between CGRP and the transmembrane domain of CLR: I284 (ECL2) and L291 (top of TM5) are the main contacts, with minor contacts at M223 (TM3) and F349 (TM6), consistent with CGRP sitting atop the TM bundle of the CLR–RAMP1 complex.","method":"Genetic code expansion with unnatural amino acid mutagenesis, photoaffinity cross-linking, fluorescein-labeled CGRP analogue, molecular modeling","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — photoaffinity cross-linking with site-specific unnatural amino acid incorporation, validated by mutagenesis and molecular modeling","pmids":["30004692"],"is_preprint":false},{"year":2019,"finding":"RAMP1 in Kupffer cells (liver-resident macrophages) is required for restraining cytokine production during immune-mediated hepatitis; RAMP1-deficient mice show exacerbated ConA-induced liver injury with increased pro-inflammatory cytokines; co-culture experiments showed RAMP1-dependent crosstalk between Kupffer cells and splenic T cells amplifies cytokine expression.","method":"RAMP1 knockout mice, Kupffer cell depletion, T cell depletion, splenectomy, adoptive transfer of splenic T cells, in vitro co-culture with cytokine measurement","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic and cell-transfer experiments establishing cell-type-specific mechanism","pmids":["30462657"],"is_preprint":false},{"year":2019,"finding":"RAMP1 signaling is required for stress-induced hematopoietic repopulation; RAMP1-deficient bone marrow has decreased repopulation capacity with enhanced ROS production and apoptosis under proliferative stress, while steady-state hematopoiesis is maintained. Continuous CGRP exposure reduces BM immature hematopoietic cell numbers via CRLR/RAMP1.","method":"RAMP1 knockout mice, bone marrow transplantation repopulation assay, ROS measurement, apoptosis assays, chronic CGRP administration","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with functional BM repopulation assay; single lab","pmids":["30674976"],"is_preprint":false},{"year":2020,"finding":"RAMP1 deficiency impairs liver regeneration after partial hepatectomy and CCl4 injury; mechanistically, RAMP1 loss leads to hyperphosphorylation of YAP on Ser127 and Ser397 (inactivating modifications), reducing YAP/TAZ protein levels and suppressing YAP-controlled cell cycle regulators. CGRP treatment of liver slice cultures and primary human hepatocytes increased YAP protein and reduced its phosphorylation.","method":"RAMP1 knockout mice, 70% partial hepatectomy model, CCl4 chronic injury model, Western blot for pYAP, in vitro CGRP stimulation of human/mouse liver slices and primary hepatocytes","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO with mechanistic in vitro validation in human primary cells, multiple orthogonal methods","pmids":["32329113"],"is_preprint":false},{"year":2020,"finding":"RAMP1 signaling in immune cells (specifically CD4+ T cells) promotes inflammation-induced lymphangiogenesis by driving VEGF-C and VEGF-D expression; RAMP1-deficient macrophages display a pro-inflammatory M1 phenotype shift, impairing lymphatic vessel growth.","method":"RAMP1 knockout mice, LPS-induced peritoneal lymphangiogenesis model, CD4+ cell depletion, immunohistochemistry, qRT-PCR for VEGF-C/D","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with cell-depletion epistasis and molecular readouts; single lab","pmids":["31911634"],"is_preprint":false},{"year":2022,"finding":"Intestinal goblet cells express RAMP1, which mediates CGRP signaling from Nav1.8+ nociceptor neurons to drive rapid goblet cell emptying and mucus secretion. Loss of epithelial RAMP1 increases susceptibility to colitis; CGRP administration rescues nociceptor-ablated mice from colitis, establishing a direct nociceptor–goblet cell axis requiring RAMP1.","method":"Mouse nociceptor ablation, chemogenetic nociceptor activation, epithelial Ramp1 conditional KO, mucus thickness measurement, colitis model, CGRP administration rescue experiments","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal genetic models (nociceptor ablation, conditional epithelial KO), rescue experiment, defined cellular mechanism","pmids":["36243004"],"is_preprint":false},{"year":2022,"finding":"RAMP1 undergoes C-mannosylation at Trp56, a modification that enhances RAMP1 protein stability and promotes cell migration activity, but does not affect RAMP1 trafficking to the plasma membrane with CLR.","method":"Mass spectrometry identification of C-mannosylation, mutagenesis of Trp56, protein stability assays, cell migration assays","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 1–2 — MS identification of PTM with functional validation by mutagenesis; single lab","pmids":["35942636"],"is_preprint":false},{"year":2024,"finding":"CGRP–RAMP1 signaling in macrophages promotes a pro-endometriosis phenotype: CGRP stimulation impairs macrophage efferocytosis and supports endometrial cell growth in a RAMP1-dependent manner. In vivo blockade of CGRP–RAMP1 reduces mechanical hyperalgesia, spontaneous pain, and lesion size in a mouse endometriosis model.","method":"Human endometriosis samples, nonsurgical mouse model, nociceptor ablation, in vitro macrophage phenotyping with efferocytosis assays, RAMP1-dependent cell growth assays, pharmacological CGRP blockade in vivo","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 — mechanistic in vitro macrophage studies with in vivo disease model validation and human tissue confirmation","pmids":["39504351"],"is_preprint":false},{"year":2024,"finding":"CGRP–RAMP1 signaling between commensal-specific CD8+ T cells and somatosensory neurons constrains Type 17 immune responses in the skin; RAMP1 upregulation in commensal-induced T cells was observed by intravital imaging, and CGRP–RAMP1 signaling moderated T cell activation and influenced wound healing outcomes.","method":"Intravital imaging (T cell proximity to cutaneous nerve fibers), flow cytometry (RAMP1 expression on T cells), commensal colonization model, wound healing assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — intravital imaging plus genetic and functional validation across multiple readouts","pmids":["38451947"],"is_preprint":false},{"year":2024,"finding":"RAMP1 absence exacerbates liver fibrosis; mechanistically, RAMP1 deficiency impairs TGFβ1/Smad2 signaling and reduces YAP activity in liver parenchyma. In vitro, CGRP stimulation of hepatic stellate cells (LX-2) induces TGFβ1 production, downstream Smad2 signaling, α-SMA expression, collagen synthesis, and YAP nuclear translocation.","method":"RAMP1 KO murine fibrosis model, Western blot for Smad2 phosphorylation and YAP, in vitro CGRP stimulation of LX-2 cells, immunofluorescence for YAP localization","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KO with in vitro mechanistic pathway dissection; single lab","pmids":["39103072"],"is_preprint":false},{"year":2024,"finding":"RAMP1 protects hepatocytes against ischemia-reperfusion injury by inhibiting ERK/MAPK pathway activation and YAP phosphorylation; RAMP1-KO mice show increased ERK phosphorylation and YAP Ser phosphorylation, promoting apoptosis. ERK inhibitor (SCH772984) and YAP phosphorylation inhibitor (PY-60) reduced apoptosis in RAMP1-KO settings.","method":"RAMP1 KO mouse liver ischemia-reperfusion model, Western blot for pERK and pYAP, pharmacological inhibition experiments in vitro and in vivo","journal":"Journal of clinical and translational hepatology","confidence":"Medium","confidence_rationale":"Tier 2 — KO model with pharmacological rescue establishing pathway; single lab","pmids":["38638379"],"is_preprint":false},{"year":2024,"finding":"Sensory nerve-derived CGRP binds RAMP1 on dental pulp stem cells (DPSCs) to promote collective migration to injury sites, facilitating pulp repair. Sensory denervation impaired DPSC recruitment and caused ectopic mineralization; exogenous CGRP rescue and BIBN4096 antagonism confirmed RAMP1 dependence.","method":"In vivo denervation, single-cell RNA-seq, immunohistochemistry, indirect co-culture with conditioned medium from trigeminal neurons, CGRP protein and BIBN4096 treatment, collective migration assays","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — scRNA-seq discovery with in vivo and in vitro mechanistic validation; single lab","pmids":["39196292"],"is_preprint":false},{"year":2024,"finding":"Amylin receptor AMY1R (CTR+RAMP1) exhibits a basal subunit equilibrium favoring free CTR and free RAMP1; rat amylin and αCGRP agonists promote CTR–RAMP1 subunit association, and these changes in heterodimer assembly directly determine cAMP signaling phenotype.","method":"Novel biochemical assay resolving AMYR heterodimers vs free subunits, live cell membrane experiments, G protein coupling and cAMP signaling assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 — reconstitution-level biochemical assay with functional cAMP readout; preprint, single lab","pmids":["bio_10.1101_2024.10.09.617487"],"is_preprint":true},{"year":2025,"finding":"CGRP/RAMP1 signaling mediates the increase (but not the decrease) in CSD-evoked calcium signaling in a subset of meningeal macrophages, as shown by intravital two-photon imaging in reporter mice with pharmacological CGRP receptor blockade.","method":"Chronic intravital two-photon calcium imaging (Pf4Cre:GCaMP6s mice), cortical spreading depolarization induction, pharmacological CGRP/RAMP1 blockade","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — live in vivo imaging with pharmacological dissection; preprint, single lab","pmids":["bio_10.1101_2025.10.01.679335"],"is_preprint":true},{"year":2025,"finding":"RAMP1 expression in the trigeminal ganglion varies across the estrous cycle (peaks in proestrus, declines in diestrus), inversely correlating with Calca (CGRPα); estrogen upregulates Ramp1 expression in both sexes via ERβ-dependent mechanisms. In Ramp1 KO mice, cyclical variation of Calca, Ramp2, and Ramp3 is absent and basal Calca is elevated in males, demonstrating RAMP1 is required for hormonal regulation of the CGRP system.","method":"RT-qPCR across estrous cycle stages, estrogen/progesterone administration, Ramp1 KO mice (both sexes), correlation analysis with Esr2","journal":"The journal of headache and pain","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse epistasis with hormone treatment in vivo; single lab","pmids":["40528180"],"is_preprint":false}],"current_model":"RAMP1 is a single-pass transmembrane accessory protein that forms a 1:1 heterodimer with the GPCR calcitonin receptor-like receptor (CLR/CRLR), directing its trafficking to the cell surface, determining CGRP ligand specificity, and enabling G protein and β-arrestin coupling; agonist stimulation drives phosphorylation of CLR and dynamin/β-arrestin-dependent clathrin-mediated internalization of the entire CRLR–RAMP1–β-arrestin ternary complex, while key extracellular residues (including Trp74, Trp84, Y66, H97) on RAMP1 form the binding interface for both peptide agonists and small-molecule antagonists (gepants), and C-mannosylation at Trp56 stabilizes RAMP1 protein; beyond classical CGRP receptor function, RAMP1 mediates neuroimmune and neuroepithelial signaling in macrophages, goblet cells, T lymphocytes, hepatic stellate cells, and dental pulp stem cells, regulating inflammation, mucosal barrier protection, lymphangiogenesis, and tissue regeneration through downstream YAP/TAZ, TGFβ1/Smad2, ERK/MAPK, and p38MAPK pathways."},"narrative":{"teleology":[{"year":1999,"claim":"The central question of how a single GPCR (CRLR) discriminates between CGRP and adrenomedullin was resolved by showing that RAMP1 coexpression switches CRLR pharmacology to CGRP selectivity, establishing RAMP1 as a ligand-specificity determinant.","evidence":"Radioligand binding and cAMP reporter assays with RAMP1/RAMP2 coexpression in COS-7 and UMR-106 cells","pmids":["10342881"],"confidence":"High","gaps":["Structural basis of specificity switching unknown","Whether RAMP1 contacts the ligand directly was not tested"]},{"year":2001,"claim":"The question of how RAMP1 reaches the cell surface and what happens to the complex after agonist stimulation was answered: RAMP1 alone is ER-retained as a homodimer, forms a 1:1 heterodimer with CRLR for surface trafficking, and CGRP stimulation triggers dynamin- and β-arrestin-dependent internalization of the intact ternary complex.","evidence":"Subcellular fractionation, non-reducing SDS-PAGE, co-IP, dominant-negative dynamin/β-arrestin constructs, confocal imaging","pmids":["11535606"],"confidence":"High","gaps":["Post-endocytic fate of the complex (recycling vs. degradation) not determined","Phosphorylation sites on CLR driving internalization not mapped"]},{"year":2007,"claim":"Whether RAMP1 is required for CLR to engage any downstream effector was demonstrated in living cells: BRET titration showed selective CRLR–RAMP1 heterodimerization and that CRLR alone cannot recruit G proteins or β-arrestin.","evidence":"BRET with Rluc/GFP fusions, radioligand binding, cAMP assays in living cells","pmids":["17503773"],"confidence":"High","gaps":["Which G protein subtypes RAMP1 enables was not dissected","Whether RAMP1 allosterically activates CLR or merely chaperones it remained unclear"]},{"year":2006,"claim":"The three-dimensional arrangement of the RAMP1 extracellular domain—three disulfide bonds and three α-helices—was established, predicting CLR-binding and ligand-contact residues that guided subsequent mutagenesis.","evidence":"Cysteine mutagenesis combined with ab initio structure prediction and MD simulation in COS-7 cells","pmids":["16632510"],"confidence":"Medium","gaps":["Full structure was computational, not experimentally determined at atomic resolution","Predicted interface residues required functional validation"]},{"year":2009,"claim":"Systematic alanine scanning and chimera analysis mapped the RAMP1 extracellular domain into distinct functional modules: Y66/H97 for CLR trafficking, L69/T73/P85/N86/F101 for CGRP recognition, and helix 1 plus residues 62–69 for receptor association, separating trafficking from signaling determinants.","evidence":"Alanine-scanning mutagenesis, RAMP1–RAMP3 chimeras, cell-surface ELISA and cAMP assays in Cos7 cells","pmids":["19072332","20017504"],"confidence":"High","gaps":["Atomic-resolution contacts between RAMP1 and CLR not yet visualized","Whether these residues affect biased signaling was untested"]},{"year":2009,"claim":"How small-molecule antagonists (gepants) interact with the CLR–RAMP1 interface was revealed: Trp74 of RAMP1 and Met42 of CLR are critical contacts for olcegepant and telcagepant, establishing that gepants exploit the heterodimer interface rather than binding CLR alone.","evidence":"Site-directed mutagenesis of CLR and RAMP1, radioligand binding with quantitative affinity measurements for two clinical antagonists","pmids":["19914210","20188075"],"confidence":"High","gaps":["No co-crystal structure of gepant bound to the CLR–RAMP1 complex","Whether newer gepants (e.g., rimegepant, ubrogepant) share the same binding mode was not tested"]},{"year":2014,"claim":"The first in vivo loss-of-function evidence showed RAMP1 promotes airway inflammation: RAMP1-KO mice had reduced airway resistance in an asthma model, and cell-specific CLR deletion excluded smooth muscle, pointing to endothelial/inflammatory cells as the relevant RAMP1-dependent compartment.","evidence":"RAMP1 global KO and cell-specific CLR KO mice, ovalbumin sensitization, methacholine challenge","pmids":["25010197"],"confidence":"High","gaps":["Specific immune cell type mediating the effect not identified","Downstream signaling pathway in airway inflammation not dissected"]},{"year":2019,"claim":"RAMP1 was placed in neuroimmune circuits beyond classical sensory neuron biology: in Kupffer cells it restrains pro-inflammatory cytokine production during hepatitis, and in bone marrow it supports hematopoietic repopulation under proliferative stress by limiting ROS and apoptosis.","evidence":"RAMP1-KO mice with Kupffer cell/T cell depletion and adoptive transfer (hepatitis); BM transplantation repopulation and ROS assays (hematopoiesis)","pmids":["30462657","30674976"],"confidence":"High","gaps":["Whether RAMP1-dependent anti-inflammatory signaling in Kupffer cells is Gs/cAMP-mediated was not shown","Mechanism linking RAMP1 to ROS regulation in HSCs not defined"]},{"year":2020,"claim":"RAMP1-dependent CGRP signaling was connected to the Hippo pathway effector YAP: RAMP1 deficiency causes YAP hyperphosphorylation (inactivation), impairing liver regeneration, while CGRP treatment stabilizes YAP in hepatocytes; separately, RAMP1 in CD4+ T cells drives VEGF-C/D-dependent lymphangiogenesis.","evidence":"RAMP1-KO mice with partial hepatectomy and CCl4 injury; CGRP stimulation of human hepatocytes; LPS-induced lymphangiogenesis with CD4+ cell depletion","pmids":["32329113","31911634"],"confidence":"High","gaps":["How CGRP/Gs signaling inhibits LATS kinase-mediated YAP phosphorylation is unknown","Whether lymphangiogenic and hepatoprotective roles share common downstream pathways not tested"]},{"year":2022,"claim":"A direct nociceptor–epithelial signaling axis was established: nociceptor-derived CGRP acts on RAMP1 in intestinal goblet cells to trigger mucus secretion and protect against colitis, defining RAMP1 as a mucosal barrier regulator.","evidence":"Nociceptor ablation, chemogenetic activation, epithelial-specific Ramp1 conditional KO, CGRP rescue in colitis model","pmids":["36243004"],"confidence":"High","gaps":["Intracellular signaling pathway from RAMP1/CLR to mucin granule exocytosis in goblet cells not identified","Whether RAMP1 regulates other secretory epithelial cells not tested"]},{"year":2022,"claim":"C-mannosylation at Trp56 was identified as a post-translational modification that stabilizes RAMP1 protein and promotes cell migration, without affecting CLR surface trafficking, adding a new regulatory layer to RAMP1 biology.","evidence":"Mass spectrometry, Trp56 mutagenesis, protein stability and cell migration assays","pmids":["35942636"],"confidence":"Medium","gaps":["Enzyme responsible for C-mannosylation not identified","Whether this modification is regulated in physiological or pathological contexts unknown"]},{"year":2024,"claim":"RAMP1 was positioned in multiple new tissue-repair and disease contexts: it mediates macrophage dysfunction in endometriosis, constrains Type 17 immunity via CD8+ T cells in skin, promotes dental pulp stem cell migration for tissue repair, modulates hepatic fibrosis through TGFβ1/Smad2 and YAP, and protects against ischemia-reperfusion injury by restraining ERK/MAPK and YAP phosphorylation.","evidence":"Endometriosis mouse model with macrophage phenotyping; intravital imaging of T cell–nerve interactions; scRNA-seq and denervation in dental pulp; RAMP1-KO fibrosis and IR models with pharmacological rescue","pmids":["39504351","38451947","39196292","39103072","38638379"],"confidence":"High","gaps":["Whether RAMP1 signals through CLR vs. CTR (AMY1R) in each cell type is often assumed but not formally tested","Biased signaling contributions (Gs vs. β-arrestin) in tissue-specific outcomes undefined","Relative contributions of CGRP vs. amylin as endogenous ligands in non-neuronal tissues unclear"]},{"year":2025,"claim":"RAMP1 expression in trigeminal ganglia is hormonally regulated—estrogen upregulates Ramp1 via ERβ—and RAMP1 is required for estrous-cycle-dependent fluctuations in the broader CGRP system, providing a molecular basis for sex differences in migraine.","evidence":"RT-qPCR across estrous stages, estrogen/progesterone administration, Ramp1-KO mice of both sexes","pmids":["40528180"],"confidence":"Medium","gaps":["Direct ERβ binding to the Ramp1 promoter not demonstrated","Whether hormonal regulation of RAMP1 extends to peripheral tissues is unknown","Functional consequence for migraine-relevant trigeminovascular signaling not directly tested"]},{"year":null,"claim":"Key unresolved questions include: (1) how CGRP–RAMP1/CLR signaling mechanistically connects to YAP/Hippo pathway regulation, (2) whether RAMP1 pairs with CLR vs. CTR in each of the newly identified non-neuronal cell types, and (3) how biased agonism (Gs vs. β-arrestin) at the RAMP1-containing receptor contributes to divergent tissue-specific outcomes.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural basis for RAMP1-mediated biased signaling","RAMP1 partner receptor identity in macrophages, goblet cells, T cells, and stellate cells not systematically determined","Endogenous ligand hierarchy (CGRP vs. amylin vs. adrenomedullin) at RAMP1-containing receptors in non-neuronal tissues unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,5,6]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[17,23]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,4,9]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[11,13,16,20]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,2,4,9]}],"complexes":["CLR–RAMP1 (CGRP receptor)","CTR–RAMP1 (AMY1 receptor)"],"partners":["CALCRL","CALCR","ARRB1","ARRB2","YAP1","NKX3.1"],"other_free_text":[]},"mechanistic_narrative":"RAMP1 is a single-pass transmembrane accessory protein that heterodimerizes with calcitonin receptor-like receptor (CLR/CRLR) to constitute a functional CGRP receptor, governing receptor trafficking, ligand specificity, and downstream signaling. Expressed alone, RAMP1 is retained as a disulfide-linked homodimer in the ER; upon 1:1 heterodimerization with CLR, it escorts the receptor to the cell surface, where it confers CGRP selectivity over adrenomedullin and enables Gs-coupled cAMP production as well as β-arrestin recruitment and clathrin-mediated internalization of the intact CRLR–RAMP1–β-arrestin complex [PMID:10342881, PMID:11535606, PMID:17503773]. Key extracellular residues—Trp74, Trp84, Y66, H97—form the binding interface for both CGRP peptide agonists and small-molecule antagonists (gepants), while C-mannosylation at Trp56 stabilizes RAMP1 protein without affecting surface trafficking [PMID:19914210, PMID:20188075, PMID:35942636]. Beyond classical CGRP receptor pharmacology, RAMP1 transduces nociceptor-derived CGRP signals in macrophages, goblet cells, T lymphocytes, hepatic stellate cells, and dental pulp stem cells, regulating mucosal barrier protection, inflammation-induced lymphangiogenesis, liver regeneration and fibrosis, and tissue repair through downstream YAP/TAZ, TGFβ1/Smad2, and ERK/MAPK pathways [PMID:36243004, PMID:32329113, PMID:39103072, PMID:38451947]."},"prefetch_data":{"uniprot":{"accession":"O60894","full_name":"Receptor activity-modifying protein 1","aliases":["Calcitonin-receptor-like receptor activity-modifying protein 1","CRLR activity-modifying protein 1"],"length_aa":148,"mass_kda":17.0,"function":"Accessory protein that interacts with and modulates the function of G-protein coupled receptors including calcitonin gene-related peptide type 1 receptor (CALCRL) and calcitonin receptor (CALCR) (PubMed:33602864, PubMed:9620797, PubMed:35324283, PubMed:38603770). Required for the transport of CALCRL to the plasma membrane (PubMed:9620797). Together with CALCRL, form the receptor complex for the calcitonin gene-related peptides CGRP1/CALCA and CGRP2/CALCB (PubMed:33602864, PubMed:9620797). Together with CALCR, form the AMYR1 receptor complex for amylin/IAPP and CGRP1/CALCA (PubMed:35324283, PubMed:38603770)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/O60894/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RAMP1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RAMP1","total_profiled":1310},"omim":[{"mim_id":"608682","title":"ADRENOMEDULLIN 2; ADM2","url":"https://www.omim.org/entry/608682"},{"mim_id":"606121","title":"CGRP RECEPTOR COMPONENT; CRCP","url":"https://www.omim.org/entry/606121"},{"mim_id":"605155","title":"RECEPTOR ACTIVITY-MODIFYING PROTEIN 3; RAMP3","url":"https://www.omim.org/entry/605155"},{"mim_id":"605154","title":"RECEPTOR ACTIVITY-MODIFYING PROTEIN 2; RAMP2","url":"https://www.omim.org/entry/605154"},{"mim_id":"605153","title":"RECEPTOR ACTIVITY-MODIFYING PROTEIN 1; RAMP1","url":"https://www.omim.org/entry/605153"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nuclear membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":533.5},{"tissue":"endometrium 1","ntpm":693.9}],"url":"https://www.proteinatlas.org/search/RAMP1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O60894","domains":[{"cath_id":"1.10.150.510","chopping":"30-106","consensus_level":"high","plddt":96.2392,"start":30,"end":106}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60894","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60894-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60894-F1-predicted_aligned_error_v6.png","plddt_mean":89.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RAMP1","jax_strain_url":"https://www.jax.org/strain/search?query=RAMP1"},"sequence":{"accession":"O60894","fasta_url":"https://rest.uniprot.org/uniprotkb/O60894.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60894/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60894"}},"corpus_meta":[{"pmid":"18186028","id":"PMC_18186028","title":"Calcitonin receptor-like receptor (CLR), receptor 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RAMP1 competitively inhibits RAMP2-evoked ADM receptor expression, shifting receptor pharmacology to CGRP selectivity.\",\n      \"method\": \"Radioligand binding ([125I]hαCGRP, [125I]rADM), cAMP-responsive luciferase reporter assay, transient transfection in COS-7 and UMR-106 cells\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — functional reconstitution with radioligand binding and cAMP assays, replicated across two cell lines\",\n      \"pmids\": [\"10342881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"RAMP1 expressed alone is retained intracellularly in the ER and Golgi as a disulfide-linked homodimer. Upon coexpression with CRLR, RAMP1 forms a 1:1 heterodimer that traffics to the cell surface; heterodimer formation promotes intramolecular disulfide bonds within RAMP1 but does not involve intermolecular disulfide bonds between the two partners. CGRP stimulation leads to CRLR phosphorylation and dynamin- and β-arrestin-dependent internalization of the CRLR–RAMP1 complex as a stable ternary complex with β-arrestin via clathrin-coated pits.\",\n      \"method\": \"Subcellular fractionation, non-reducing SDS-PAGE, co-immunoprecipitation, dominant-negative dynamin and β-arrestin constructs, confocal immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (biochemistry, dominant-negative genetics, imaging) in a single study with rigorous controls\",\n      \"pmids\": [\"11535606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"BRET titration experiments in living cells demonstrated that CRLR and RAMP1 selectively form heterodimers; both proteins can also independently form homodimers. RAMP1 is required for CRLR to engage G proteins and β-arrestin upon CGRP stimulation—CRLR alone cannot recruit these signaling partners.\",\n      \"method\": \"Bioluminescence resonance energy transfer (BRET) with Rluc/GFP fusion proteins, radioligand binding, cAMP production assay\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — live-cell BRET with titration experiments and functional validation by radioligand binding and cAMP assays\",\n      \"pmids\": [\"17503773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Ab initio structural modeling of the RAMP1 extracellular domain determined the disulfide bond arrangement (Cys27–Cys82, Cys40–Cys72, Cys57–Cys104) by site-directed mutagenesis, and identified three α-helices (residues 29–51, 60–80, 87–100). The model predicted Phe93, Tyr100, Phe101 as a CLR-binding interface and Trp74, Phe92 as ligand-interaction residues.\",\n      \"method\": \"Site-directed mutagenesis of cysteines, ab initio structure prediction with molecular dynamics refinement, functional expression in COS-7 cells\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 for mutagenesis; Tier 4 for structural model — single lab, mutagenesis validated disulfide bonds but full structure is computational\",\n      \"pmids\": [\"16632510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Alanine mutagenesis across the RAMP1 N-terminal extracellular domain identified Y66 and H97 as critical for CLR trafficking (receptor association), while L69, T73, and residues in helix 3 (P85, N86, F101) contribute to CGRP recognition and cAMP signaling. M48 had a modest effect on CLR surface delivery.\",\n      \"method\": \"Alanine-scanning mutagenesis of 22 RAMP1 residues, cell-surface ELISA, cAMP assay in Cos7 cells\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic mutagenesis with functional readouts (trafficking and cAMP) across multiple residues\",\n      \"pmids\": [\"19072332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Non-peptide CGRP receptor antagonists BIBN4096BS (olcegepant) and MK-0974 (telcagepant) interact with the CLR–RAMP1 interface: Trp-74 of RAMP1 is a key contact for both antagonists (W74K mutation reduces BIBN4096BS affinity >300-fold and MK-0974 affinity similarly), and Met-42 of CLR N-terminal domain is critical (M42A reduces BIBN4096BS affinity 48-fold, MK-0974 ~900-fold).\",\n      \"method\": \"Site-directed mutagenesis of CLR (residues 23–63) and RAMP1 (W74K), radioligand binding and functional assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis of both receptor components with quantitative affinity measurements for two clinical antagonists\",\n      \"pmids\": [\"19914210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RAMP1 Trp-84 is critical for high-affinity binding of both non-peptide antagonists (telcagepant, olcegepant) and the peptide agonists CGRP and CGRP(8-37); Arg-67 of RAMP1 is selectively important for telcagepant but not the BIBN4096BS analog, indicating distinct but overlapping binding modes within the RAMP1 extracellular domain.\",\n      \"method\": \"Alanine replacement mutagenesis of RAMP1 residues, radioligand binding, functional cAMP assay in Cos7 cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic mutagenesis with binding and functional assays, confirms and extends prior structural data\",\n      \"pmids\": [\"20188075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RAMP1–RAMP3 chimera analysis showed that helix 1 of RAMP1 and residues 62–69 of helix 2 are required for CLR trafficking (association), while residues 86–89 of RAMP1 helix 3 contribute to peptide (αCGRP, adrenomedullin) potency without affecting βCGRP, and residues 90–94 have dual roles in CLR recognition and CGRP binding.\",\n      \"method\": \"RAMP1–RAMP3 chimera construction, CLR trafficking assay (cell-surface ELISA), agonist-stimulated cAMP assay in Cos7 cells\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — chimeric protein analysis with trafficking and functional readouts across 26 constructs\",\n      \"pmids\": [\"20017504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Position 74 of RAMP1 (Trp74) governs differential peptide pharmacology: substitutions alter AM potency at the CGRP receptor (CLR/RAMP1) differently from RAMP3 position 74 (Glu74), confirming this position as a determinant of ligand discrimination between adrenomedullin and CGRP at their respective receptors.\",\n      \"method\": \"Site-directed mutagenesis of position 74 in RAMP1 and RAMP3 with multiple amino acid substitutions, cAMP assay in Cos7 cells, cell-surface ELISA\",\n      \"journal\": \"Peptides\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis with functional assays; single lab study\",\n      \"pmids\": [\"21402116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RAMP1 overexpression in MG-63 osteoblast-like cells increases CRLR surface expression and enhances CGRP-induced osteogenic differentiation (alkaline phosphatase activity, collagen I expression, mineralization), demonstrating RAMP1's role in promoting CRLR membrane localization and amplifying CGRP-mediated osteoblast differentiation.\",\n      \"method\": \"Stable transfection with RAMP1 eukaryotic expression vector, RT-PCR, Western blot, immunofluorescence, ALP activity assay, Alizarin Red staining\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — gain-of-function with multiple differentiation readouts; single lab\",\n      \"pmids\": [\"22949393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NKX3.1 transcription factor directly represses RAMP1 gene expression in prostate cells; RAMP1 knockdown reduces prostate cancer cell proliferation and tumorigenicity in vitro and in vivo, and decreases MEK1 expression and ERK1/2 phosphorylation, placing RAMP1 upstream of the MAPK signaling pathway in prostate cancer.\",\n      \"method\": \"ChIP-seq (NKX3.1 binding to RAMP1 locus), shRNA knockdown, gene expression profiling, xenograft tumor models, Western blot for pERK1/2\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq plus loss-of-function with in vivo validation and pathway analysis\",\n      \"pmids\": [\"23867798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RAMP1-deficient mice show reduced airway resistance and airway inflammation in an ovalbumin-sensitized asthma model; loss of CLR from smooth muscle cells did not affect airway resistance, indicating CGRP signaling through RAMP1/CLR promotes asthma pathology via endothelial and inflammatory cells rather than smooth muscle.\",\n      \"method\": \"RAMP1 knockout mouse (exon 3 deletion), cell-specific CLR knockout, methacholine challenge, airway resistance measurement, histological assessment of inflammation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with cell-type-specific epistasis, defined physiological phenotype\",\n      \"pmids\": [\"25010197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Photoaffinity cross-linking using unnatural amino acid (p-azido-L-phenylalanine) incorporated into CLR ECL2 identified key contacts between CGRP and the transmembrane domain of CLR: I284 (ECL2) and L291 (top of TM5) are the main contacts, with minor contacts at M223 (TM3) and F349 (TM6), consistent with CGRP sitting atop the TM bundle of the CLR–RAMP1 complex.\",\n      \"method\": \"Genetic code expansion with unnatural amino acid mutagenesis, photoaffinity cross-linking, fluorescein-labeled CGRP analogue, molecular modeling\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — photoaffinity cross-linking with site-specific unnatural amino acid incorporation, validated by mutagenesis and molecular modeling\",\n      \"pmids\": [\"30004692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RAMP1 in Kupffer cells (liver-resident macrophages) is required for restraining cytokine production during immune-mediated hepatitis; RAMP1-deficient mice show exacerbated ConA-induced liver injury with increased pro-inflammatory cytokines; co-culture experiments showed RAMP1-dependent crosstalk between Kupffer cells and splenic T cells amplifies cytokine expression.\",\n      \"method\": \"RAMP1 knockout mice, Kupffer cell depletion, T cell depletion, splenectomy, adoptive transfer of splenic T cells, in vitro co-culture with cytokine measurement\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic and cell-transfer experiments establishing cell-type-specific mechanism\",\n      \"pmids\": [\"30462657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RAMP1 signaling is required for stress-induced hematopoietic repopulation; RAMP1-deficient bone marrow has decreased repopulation capacity with enhanced ROS production and apoptosis under proliferative stress, while steady-state hematopoiesis is maintained. Continuous CGRP exposure reduces BM immature hematopoietic cell numbers via CRLR/RAMP1.\",\n      \"method\": \"RAMP1 knockout mice, bone marrow transplantation repopulation assay, ROS measurement, apoptosis assays, chronic CGRP administration\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with functional BM repopulation assay; single lab\",\n      \"pmids\": [\"30674976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RAMP1 deficiency impairs liver regeneration after partial hepatectomy and CCl4 injury; mechanistically, RAMP1 loss leads to hyperphosphorylation of YAP on Ser127 and Ser397 (inactivating modifications), reducing YAP/TAZ protein levels and suppressing YAP-controlled cell cycle regulators. CGRP treatment of liver slice cultures and primary human hepatocytes increased YAP protein and reduced its phosphorylation.\",\n      \"method\": \"RAMP1 knockout mice, 70% partial hepatectomy model, CCl4 chronic injury model, Western blot for pYAP, in vitro CGRP stimulation of human/mouse liver slices and primary hepatocytes\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with mechanistic in vitro validation in human primary cells, multiple orthogonal methods\",\n      \"pmids\": [\"32329113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RAMP1 signaling in immune cells (specifically CD4+ T cells) promotes inflammation-induced lymphangiogenesis by driving VEGF-C and VEGF-D expression; RAMP1-deficient macrophages display a pro-inflammatory M1 phenotype shift, impairing lymphatic vessel growth.\",\n      \"method\": \"RAMP1 knockout mice, LPS-induced peritoneal lymphangiogenesis model, CD4+ cell depletion, immunohistochemistry, qRT-PCR for VEGF-C/D\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with cell-depletion epistasis and molecular readouts; single lab\",\n      \"pmids\": [\"31911634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Intestinal goblet cells express RAMP1, which mediates CGRP signaling from Nav1.8+ nociceptor neurons to drive rapid goblet cell emptying and mucus secretion. Loss of epithelial RAMP1 increases susceptibility to colitis; CGRP administration rescues nociceptor-ablated mice from colitis, establishing a direct nociceptor–goblet cell axis requiring RAMP1.\",\n      \"method\": \"Mouse nociceptor ablation, chemogenetic nociceptor activation, epithelial Ramp1 conditional KO, mucus thickness measurement, colitis model, CGRP administration rescue experiments\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal genetic models (nociceptor ablation, conditional epithelial KO), rescue experiment, defined cellular mechanism\",\n      \"pmids\": [\"36243004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RAMP1 undergoes C-mannosylation at Trp56, a modification that enhances RAMP1 protein stability and promotes cell migration activity, but does not affect RAMP1 trafficking to the plasma membrane with CLR.\",\n      \"method\": \"Mass spectrometry identification of C-mannosylation, mutagenesis of Trp56, protein stability assays, cell migration assays\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — MS identification of PTM with functional validation by mutagenesis; single lab\",\n      \"pmids\": [\"35942636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CGRP–RAMP1 signaling in macrophages promotes a pro-endometriosis phenotype: CGRP stimulation impairs macrophage efferocytosis and supports endometrial cell growth in a RAMP1-dependent manner. In vivo blockade of CGRP–RAMP1 reduces mechanical hyperalgesia, spontaneous pain, and lesion size in a mouse endometriosis model.\",\n      \"method\": \"Human endometriosis samples, nonsurgical mouse model, nociceptor ablation, in vitro macrophage phenotyping with efferocytosis assays, RAMP1-dependent cell growth assays, pharmacological CGRP blockade in vivo\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic in vitro macrophage studies with in vivo disease model validation and human tissue confirmation\",\n      \"pmids\": [\"39504351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CGRP–RAMP1 signaling between commensal-specific CD8+ T cells and somatosensory neurons constrains Type 17 immune responses in the skin; RAMP1 upregulation in commensal-induced T cells was observed by intravital imaging, and CGRP–RAMP1 signaling moderated T cell activation and influenced wound healing outcomes.\",\n      \"method\": \"Intravital imaging (T cell proximity to cutaneous nerve fibers), flow cytometry (RAMP1 expression on T cells), commensal colonization model, wound healing assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — intravital imaging plus genetic and functional validation across multiple readouts\",\n      \"pmids\": [\"38451947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RAMP1 absence exacerbates liver fibrosis; mechanistically, RAMP1 deficiency impairs TGFβ1/Smad2 signaling and reduces YAP activity in liver parenchyma. In vitro, CGRP stimulation of hepatic stellate cells (LX-2) induces TGFβ1 production, downstream Smad2 signaling, α-SMA expression, collagen synthesis, and YAP nuclear translocation.\",\n      \"method\": \"RAMP1 KO murine fibrosis model, Western blot for Smad2 phosphorylation and YAP, in vitro CGRP stimulation of LX-2 cells, immunofluorescence for YAP localization\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with in vitro mechanistic pathway dissection; single lab\",\n      \"pmids\": [\"39103072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RAMP1 protects hepatocytes against ischemia-reperfusion injury by inhibiting ERK/MAPK pathway activation and YAP phosphorylation; RAMP1-KO mice show increased ERK phosphorylation and YAP Ser phosphorylation, promoting apoptosis. ERK inhibitor (SCH772984) and YAP phosphorylation inhibitor (PY-60) reduced apoptosis in RAMP1-KO settings.\",\n      \"method\": \"RAMP1 KO mouse liver ischemia-reperfusion model, Western blot for pERK and pYAP, pharmacological inhibition experiments in vitro and in vivo\",\n      \"journal\": \"Journal of clinical and translational hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO model with pharmacological rescue establishing pathway; single lab\",\n      \"pmids\": [\"38638379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Sensory nerve-derived CGRP binds RAMP1 on dental pulp stem cells (DPSCs) to promote collective migration to injury sites, facilitating pulp repair. Sensory denervation impaired DPSC recruitment and caused ectopic mineralization; exogenous CGRP rescue and BIBN4096 antagonism confirmed RAMP1 dependence.\",\n      \"method\": \"In vivo denervation, single-cell RNA-seq, immunohistochemistry, indirect co-culture with conditioned medium from trigeminal neurons, CGRP protein and BIBN4096 treatment, collective migration assays\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — scRNA-seq discovery with in vivo and in vitro mechanistic validation; single lab\",\n      \"pmids\": [\"39196292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Amylin receptor AMY1R (CTR+RAMP1) exhibits a basal subunit equilibrium favoring free CTR and free RAMP1; rat amylin and αCGRP agonists promote CTR–RAMP1 subunit association, and these changes in heterodimer assembly directly determine cAMP signaling phenotype.\",\n      \"method\": \"Novel biochemical assay resolving AMYR heterodimers vs free subunits, live cell membrane experiments, G protein coupling and cAMP signaling assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution-level biochemical assay with functional cAMP readout; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2024.10.09.617487\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CGRP/RAMP1 signaling mediates the increase (but not the decrease) in CSD-evoked calcium signaling in a subset of meningeal macrophages, as shown by intravital two-photon imaging in reporter mice with pharmacological CGRP receptor blockade.\",\n      \"method\": \"Chronic intravital two-photon calcium imaging (Pf4Cre:GCaMP6s mice), cortical spreading depolarization induction, pharmacological CGRP/RAMP1 blockade\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — live in vivo imaging with pharmacological dissection; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.10.01.679335\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RAMP1 expression in the trigeminal ganglion varies across the estrous cycle (peaks in proestrus, declines in diestrus), inversely correlating with Calca (CGRPα); estrogen upregulates Ramp1 expression in both sexes via ERβ-dependent mechanisms. In Ramp1 KO mice, cyclical variation of Calca, Ramp2, and Ramp3 is absent and basal Calca is elevated in males, demonstrating RAMP1 is required for hormonal regulation of the CGRP system.\",\n      \"method\": \"RT-qPCR across estrous cycle stages, estrogen/progesterone administration, Ramp1 KO mice (both sexes), correlation analysis with Esr2\",\n      \"journal\": \"The journal of headache and pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse epistasis with hormone treatment in vivo; single lab\",\n      \"pmids\": [\"40528180\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RAMP1 is a single-pass transmembrane accessory protein that forms a 1:1 heterodimer with the GPCR calcitonin receptor-like receptor (CLR/CRLR), directing its trafficking to the cell surface, determining CGRP ligand specificity, and enabling G protein and β-arrestin coupling; agonist stimulation drives phosphorylation of CLR and dynamin/β-arrestin-dependent clathrin-mediated internalization of the entire CRLR–RAMP1–β-arrestin ternary complex, while key extracellular residues (including Trp74, Trp84, Y66, H97) on RAMP1 form the binding interface for both peptide agonists and small-molecule antagonists (gepants), and C-mannosylation at Trp56 stabilizes RAMP1 protein; beyond classical CGRP receptor function, RAMP1 mediates neuroimmune and neuroepithelial signaling in macrophages, goblet cells, T lymphocytes, hepatic stellate cells, and dental pulp stem cells, regulating inflammation, mucosal barrier protection, lymphangiogenesis, and tissue regeneration through downstream YAP/TAZ, TGFβ1/Smad2, ERK/MAPK, and p38MAPK pathways.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RAMP1 is a single-pass transmembrane accessory protein that heterodimerizes with calcitonin receptor-like receptor (CLR/CRLR) to constitute a functional CGRP receptor, governing receptor trafficking, ligand specificity, and downstream signaling. Expressed alone, RAMP1 is retained as a disulfide-linked homodimer in the ER; upon 1:1 heterodimerization with CLR, it escorts the receptor to the cell surface, where it confers CGRP selectivity over adrenomedullin and enables Gs-coupled cAMP production as well as β-arrestin recruitment and clathrin-mediated internalization of the intact CRLR–RAMP1–β-arrestin complex [PMID:10342881, PMID:11535606, PMID:17503773]. Key extracellular residues—Trp74, Trp84, Y66, H97—form the binding interface for both CGRP peptide agonists and small-molecule antagonists (gepants), while C-mannosylation at Trp56 stabilizes RAMP1 protein without affecting surface trafficking [PMID:19914210, PMID:20188075, PMID:35942636]. Beyond classical CGRP receptor pharmacology, RAMP1 transduces nociceptor-derived CGRP signals in macrophages, goblet cells, T lymphocytes, hepatic stellate cells, and dental pulp stem cells, regulating mucosal barrier protection, inflammation-induced lymphangiogenesis, liver regeneration and fibrosis, and tissue repair through downstream YAP/TAZ, TGFβ1/Smad2, and ERK/MAPK pathways [PMID:36243004, PMID:32329113, PMID:39103072, PMID:38451947].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"The central question of how a single GPCR (CRLR) discriminates between CGRP and adrenomedullin was resolved by showing that RAMP1 coexpression switches CRLR pharmacology to CGRP selectivity, establishing RAMP1 as a ligand-specificity determinant.\",\n      \"evidence\": \"Radioligand binding and cAMP reporter assays with RAMP1/RAMP2 coexpression in COS-7 and UMR-106 cells\",\n      \"pmids\": [\"10342881\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of specificity switching unknown\", \"Whether RAMP1 contacts the ligand directly was not tested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"The question of how RAMP1 reaches the cell surface and what happens to the complex after agonist stimulation was answered: RAMP1 alone is ER-retained as a homodimer, forms a 1:1 heterodimer with CRLR for surface trafficking, and CGRP stimulation triggers dynamin- and β-arrestin-dependent internalization of the intact ternary complex.\",\n      \"evidence\": \"Subcellular fractionation, non-reducing SDS-PAGE, co-IP, dominant-negative dynamin/β-arrestin constructs, confocal imaging\",\n      \"pmids\": [\"11535606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Post-endocytic fate of the complex (recycling vs. degradation) not determined\", \"Phosphorylation sites on CLR driving internalization not mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Whether RAMP1 is required for CLR to engage any downstream effector was demonstrated in living cells: BRET titration showed selective CRLR–RAMP1 heterodimerization and that CRLR alone cannot recruit G proteins or β-arrestin.\",\n      \"evidence\": \"BRET with Rluc/GFP fusions, radioligand binding, cAMP assays in living cells\",\n      \"pmids\": [\"17503773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which G protein subtypes RAMP1 enables was not dissected\", \"Whether RAMP1 allosterically activates CLR or merely chaperones it remained unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The three-dimensional arrangement of the RAMP1 extracellular domain—three disulfide bonds and three α-helices—was established, predicting CLR-binding and ligand-contact residues that guided subsequent mutagenesis.\",\n      \"evidence\": \"Cysteine mutagenesis combined with ab initio structure prediction and MD simulation in COS-7 cells\",\n      \"pmids\": [\"16632510\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Full structure was computational, not experimentally determined at atomic resolution\", \"Predicted interface residues required functional validation\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Systematic alanine scanning and chimera analysis mapped the RAMP1 extracellular domain into distinct functional modules: Y66/H97 for CLR trafficking, L69/T73/P85/N86/F101 for CGRP recognition, and helix 1 plus residues 62–69 for receptor association, separating trafficking from signaling determinants.\",\n      \"evidence\": \"Alanine-scanning mutagenesis, RAMP1–RAMP3 chimeras, cell-surface ELISA and cAMP assays in Cos7 cells\",\n      \"pmids\": [\"19072332\", \"20017504\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution contacts between RAMP1 and CLR not yet visualized\", \"Whether these residues affect biased signaling was untested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"How small-molecule antagonists (gepants) interact with the CLR–RAMP1 interface was revealed: Trp74 of RAMP1 and Met42 of CLR are critical contacts for olcegepant and telcagepant, establishing that gepants exploit the heterodimer interface rather than binding CLR alone.\",\n      \"evidence\": \"Site-directed mutagenesis of CLR and RAMP1, radioligand binding with quantitative affinity measurements for two clinical antagonists\",\n      \"pmids\": [\"19914210\", \"20188075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal structure of gepant bound to the CLR–RAMP1 complex\", \"Whether newer gepants (e.g., rimegepant, ubrogepant) share the same binding mode was not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The first in vivo loss-of-function evidence showed RAMP1 promotes airway inflammation: RAMP1-KO mice had reduced airway resistance in an asthma model, and cell-specific CLR deletion excluded smooth muscle, pointing to endothelial/inflammatory cells as the relevant RAMP1-dependent compartment.\",\n      \"evidence\": \"RAMP1 global KO and cell-specific CLR KO mice, ovalbumin sensitization, methacholine challenge\",\n      \"pmids\": [\"25010197\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific immune cell type mediating the effect not identified\", \"Downstream signaling pathway in airway inflammation not dissected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"RAMP1 was placed in neuroimmune circuits beyond classical sensory neuron biology: in Kupffer cells it restrains pro-inflammatory cytokine production during hepatitis, and in bone marrow it supports hematopoietic repopulation under proliferative stress by limiting ROS and apoptosis.\",\n      \"evidence\": \"RAMP1-KO mice with Kupffer cell/T cell depletion and adoptive transfer (hepatitis); BM transplantation repopulation and ROS assays (hematopoiesis)\",\n      \"pmids\": [\"30462657\", \"30674976\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RAMP1-dependent anti-inflammatory signaling in Kupffer cells is Gs/cAMP-mediated was not shown\", \"Mechanism linking RAMP1 to ROS regulation in HSCs not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"RAMP1-dependent CGRP signaling was connected to the Hippo pathway effector YAP: RAMP1 deficiency causes YAP hyperphosphorylation (inactivation), impairing liver regeneration, while CGRP treatment stabilizes YAP in hepatocytes; separately, RAMP1 in CD4+ T cells drives VEGF-C/D-dependent lymphangiogenesis.\",\n      \"evidence\": \"RAMP1-KO mice with partial hepatectomy and CCl4 injury; CGRP stimulation of human hepatocytes; LPS-induced lymphangiogenesis with CD4+ cell depletion\",\n      \"pmids\": [\"32329113\", \"31911634\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CGRP/Gs signaling inhibits LATS kinase-mediated YAP phosphorylation is unknown\", \"Whether lymphangiogenic and hepatoprotective roles share common downstream pathways not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A direct nociceptor–epithelial signaling axis was established: nociceptor-derived CGRP acts on RAMP1 in intestinal goblet cells to trigger mucus secretion and protect against colitis, defining RAMP1 as a mucosal barrier regulator.\",\n      \"evidence\": \"Nociceptor ablation, chemogenetic activation, epithelial-specific Ramp1 conditional KO, CGRP rescue in colitis model\",\n      \"pmids\": [\"36243004\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular signaling pathway from RAMP1/CLR to mucin granule exocytosis in goblet cells not identified\", \"Whether RAMP1 regulates other secretory epithelial cells not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"C-mannosylation at Trp56 was identified as a post-translational modification that stabilizes RAMP1 protein and promotes cell migration, without affecting CLR surface trafficking, adding a new regulatory layer to RAMP1 biology.\",\n      \"evidence\": \"Mass spectrometry, Trp56 mutagenesis, protein stability and cell migration assays\",\n      \"pmids\": [\"35942636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzyme responsible for C-mannosylation not identified\", \"Whether this modification is regulated in physiological or pathological contexts unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"RAMP1 was positioned in multiple new tissue-repair and disease contexts: it mediates macrophage dysfunction in endometriosis, constrains Type 17 immunity via CD8+ T cells in skin, promotes dental pulp stem cell migration for tissue repair, modulates hepatic fibrosis through TGFβ1/Smad2 and YAP, and protects against ischemia-reperfusion injury by restraining ERK/MAPK and YAP phosphorylation.\",\n      \"evidence\": \"Endometriosis mouse model with macrophage phenotyping; intravital imaging of T cell–nerve interactions; scRNA-seq and denervation in dental pulp; RAMP1-KO fibrosis and IR models with pharmacological rescue\",\n      \"pmids\": [\"39504351\", \"38451947\", \"39196292\", \"39103072\", \"38638379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RAMP1 signals through CLR vs. CTR (AMY1R) in each cell type is often assumed but not formally tested\", \"Biased signaling contributions (Gs vs. β-arrestin) in tissue-specific outcomes undefined\", \"Relative contributions of CGRP vs. amylin as endogenous ligands in non-neuronal tissues unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"RAMP1 expression in trigeminal ganglia is hormonally regulated—estrogen upregulates Ramp1 via ERβ—and RAMP1 is required for estrous-cycle-dependent fluctuations in the broader CGRP system, providing a molecular basis for sex differences in migraine.\",\n      \"evidence\": \"RT-qPCR across estrous stages, estrogen/progesterone administration, Ramp1-KO mice of both sexes\",\n      \"pmids\": [\"40528180\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ERβ binding to the Ramp1 promoter not demonstrated\", \"Whether hormonal regulation of RAMP1 extends to peripheral tissues is unknown\", \"Functional consequence for migraine-relevant trigeminovascular signaling not directly tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: (1) how CGRP–RAMP1/CLR signaling mechanistically connects to YAP/Hippo pathway regulation, (2) whether RAMP1 pairs with CLR vs. CTR in each of the newly identified non-neuronal cell types, and (3) how biased agonism (Gs vs. β-arrestin) at the RAMP1-containing receptor contributes to divergent tissue-specific outcomes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural basis for RAMP1-mediated biased signaling\", \"RAMP1 partner receptor identity in macrophages, goblet cells, T cells, and stellate cells not systematically determined\", \"Endogenous ligand hierarchy (CGRP vs. amylin vs. adrenomedullin) at RAMP1-containing receptors in non-neuronal tissues unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 5, 6]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [17, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 4, 9]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [0, 2, 5, 6, 10, 15, 22]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11, 13, 16, 20]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 2, 4, 9]}\n    ],\n    \"complexes\": [\n      \"CLR–RAMP1 (CGRP receptor)\",\n      \"CTR–RAMP1 (AMY1 receptor)\"\n    ],\n    \"partners\": [\n      \"CALCRL\",\n      \"CALCR\",\n      \"ARRB1\",\n      \"ARRB2\",\n      \"YAP1\",\n      \"NKX3.1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}