Affinage

RAMP1

Receptor activity-modifying protein 1 · UniProt O60894

Length
148 aa
Mass
17.0 kDa
Annotated
2026-06-10
63 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAMP1 is a single-pass transmembrane accessory protein that confers ligand selectivity onto the calcitonin receptor-like receptor (CLR/CRLR): coexpression of RAMP1 converts CLR from an adrenomedullin receptor into a functional CGRP receptor by generating high-affinity CGRP binding sites and CGRP-stimulated cAMP signaling, while competing with RAMP2 for CLR association (PMID:10342881). RAMP1 is required for CLR to reach the cell surface—expressed alone it is retained in the ER/Golgi as a disulfide-linked homodimer, but with CLR it forms a 1:1 heterodimer that traffics to the plasma membrane and engages G proteins and β-arrestin upon CGRP stimulation, driving dynamin- and β-arrestin–dependent clathrin-mediated endocytosis of a stable CLR/RAMP1/β-arrestin ternary complex (PMID:11535606, PMID:17503773). The RAMP1 extracellular domain adopts a three-helix, disulfide-stabilized fold (PMID:16632510) in which discrete residues partition into a CLR-recognition surface governing receptor trafficking (Tyr66, His97, helix 1) and a CGRP-recognition surface tuning agonist potency (Leu69, Thr73, residues 86–94) (PMID:19072332, PMID:20017504); residues at the CLR/RAMP1 extracellular interface, notably RAMP1 Trp74 and Trp84, form the binding site for clinically used non-peptide antagonists (BIBN4096BS, telcagepant/MK-0974) (PMID:19914210, PMID:20188075). Receptor abundance is set by RAMP1 levels, and post-translational C-mannosylation at Trp56 enhances RAMP1 stability and cell migration without affecting CLR trafficking (PMID:35942636, PMID:22949393). Beyond receptor assembly, RAMP1 transduces CGRP-driven neuroimmune and tissue-repair programs: it shapes macrophage and T-cell phenotypes and lymphangiogenesis (PMID:31911634, PMID:29078910, PMID:39504351), protects the gut barrier through goblet-cell mucus secretion (PMID:36243004), and governs liver biology bidirectionally via YAP/TAZ and TGFβ1/Smad2 signaling—supporting regeneration and limiting ischemia-reperfusion injury while promoting fibrosis (PMID:32329113, PMID:39103072, PMID:38638379). RAMP1 expression is transcriptionally repressed by NKX3.1 and regulated by estrogen, linking it to prostate cancer MAPK signaling and to cyclical hormonal control of the CGRP system (PMID:23867798, PMID:40528180).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1999 High

    Established the founding function of RAMP1: it is the molecular switch that determines CLR ligand identity, answering why CLR can act as either an adrenomedullin or a CGRP receptor.

    Evidence Radioligand binding and CRE-luciferase cAMP assays with CRLR/RAMP1/RAMP2 combinations in COS-7 and UMR-106 cells

    PMID:10342881

    Open questions at the time
    • Did not resolve the structural basis of selectivity
    • Did not address trafficking or signaling beyond cAMP
  2. 2001 High

    Showed RAMP1 is an obligate chaperone for CLR surface delivery and defined the agonist-induced endocytic fate of the receptor, explaining how the heterodimer is assembled and internalized.

    Evidence Subcellular fractionation, co-IP, disulfide analysis, and internalization assays with dominant-negative dynamin/β-arrestin in transfected cells

    PMID:11535606

    Open questions at the time
    • Stoichiometry of the signaling complex not structurally resolved
    • Did not map ligand-contact residues
  3. 2007 High

    Demonstrated in living cells that CLR/RAMP1 heterodimerization is selective and that a trafficking-deficient RAMP1 mutant still binds CLR, distinguishing complex conformation from heterodimerization per se.

    Evidence BRET titration, radioligand binding, cAMP assays, and mutagenesis in living cells

    PMID:17503773

    Open questions at the time
    • Conformational defect not structurally defined
    • Homodimer functional role unresolved
  4. 2006 Medium

    Provided the first structural framework for the RAMP1 extracellular domain and assigned its disulfide bonds, enabling residue-level interpretation of CLR and ligand contacts.

    Evidence Ab initio molecular modeling with site-directed mutagenesis to map disulfide bonds

    PMID:16632510

    Open questions at the time
    • No experimental crystal structure
    • Modeled interface predictions required functional validation
  5. 2010 Medium

    Mapped RAMP1 surface into separable CLR-recognition and CGRP-recognition determinants, explaining how a single accessory protein controls both trafficking and pharmacology.

    Evidence Alanine scanning and RAMP1-RAMP3 chimera analysis with cell-surface ELISA and cAMP assays in COS-7 cells

    PMID:19072332 PMID:20017504

    Open questions at the time
    • Contributions inferred functionally, not from a co-structure
    • Did not resolve allosteric coupling between sites
  6. 2010 High

    Localized the binding site of clinical non-peptide CGRP antagonists to the CLR/RAMP1 extracellular interface, identifying RAMP1 Trp74/Trp84 as key contacts and providing the pharmacological rationale for the receptor as a migraine drug target.

    Evidence Site-directed/alanine mutagenesis of RAMP1 and CLR with quantitative radioligand binding for BIBN4096BS, telcagepant, and MK-0974

    PMID:19914210 PMID:20188075

    Open questions at the time
    • Antagonist poses inferred from affinity shifts rather than direct structure
    • Position-74 contributions to AM vs CGRP pharmacology only partly resolved (21402116)
  7. 2018 High

    Defined the transmembrane CGRP-binding contacts of the activated receptor, extending the ligand interface from the RAMP1/CLR ectodomain into the CLR TM bundle.

    Evidence Genetic code expansion/unnatural amino acid mutagenesis with photoaffinity cross-linking and CGRP analogue validation

    PMID:30004692

    Open questions at the time
    • RAMP1 contribution to TM-bundle contacts not directly addressed
    • Full activated-state structure not solved here
  8. 2013 Medium

    Linked RAMP1 abundance to disease via transcriptional control, showing NKX3.1 directly represses RAMP1 and that RAMP1 supports prostate cancer proliferation through MAPK signaling.

    Evidence ChIP-seq, Nkx3.1 KO mice, RAMP1 shRNA knockdown with in vitro/in vivo tumorigenicity and pathway readouts

    PMID:23867798

    Open questions at the time
    • Whether MAPK effects are CGRP-ligand-dependent not established
    • Mechanism connecting RAMP1 to MEK1/ERK not fully defined
  9. 2014 Medium

    Moved RAMP1 from receptor biochemistry into in vivo physiology, showing CGRP/RAMP1 signaling drives airway inflammation through non-smooth-muscle cells.

    Evidence RAMP1 KO mice and smooth-muscle-specific CLR mice in an ovalbumin asthma model with airway resistance and inflammatory readouts

    PMID:25010197

    Open questions at the time
    • Specific endothelial/immune cell type not pinpointed
    • Downstream signaling in those cells not defined
  10. 2019 Medium

    Established RAMP1 as a broad regulator of immune and metabolic physiology, controlling macrophage polarization, T-cell-driven lymphangiogenesis, amylin anorectic signaling, and stress hematopoiesis.

    Evidence RAMP1 (and RAMP3) KO mice across sepsis, lymphedema/lymphangiogenesis, feeding, and bone marrow transplantation models with cell-depletion and in vitro stimulation

    PMID:22656887 PMID:29078910 PMID:30462657 PMID:30674976 PMID:31881259 PMID:31911634

    Open questions at the time
    • Cell-autonomous vs systemic CGRP sources often unresolved
    • Downstream signaling effectors largely correlative across these models
  11. 2022 Medium

    Identified C-mannosylation at Trp56 as a post-translational determinant of RAMP1 stability and migration, separable from its CLR-trafficking function.

    Evidence Mass spectrometry site identification with C-mannosylation-deficient mutants in stability and migration assays

    PMID:35942636

    Open questions at the time
    • Migration mechanism downstream of C-mannosylation unknown
    • Physiological context of the modification not tested in vivo
  12. 2022 High

    Demonstrated direct neuro-epithelial signaling, with nociceptor CGRP acting on goblet-cell RAMP1 to drive mucus secretion and protect against colitis.

    Evidence Epithelial-specific RAMP1 KO, nociceptor ablation, chemogenetic activation, and DSS colitis with CGRP rescue

    PMID:36243004

    Open questions at the time
    • Intracellular pathway from RAMP1 to mucin exocytosis not defined
    • Human relevance based on expression rather than function
  13. 2024 High

    Defined RAMP1 as a context-dependent hub in liver injury, supporting regeneration and limiting ischemia-reperfusion damage while promoting fibrosis, all converging on YAP/TAZ and TGFβ1/Smad2 signaling.

    Evidence RAMP1 KO mice in hepatectomy, CCl4, ischemia-reperfusion, and fibrosis models with ERK/YAP/Smad2 readouts and CGRP/inhibitor rescue in slices, primary hepatocytes, and LX-2 cells

    PMID:32329113 PMID:38638379 PMID:39103072

    Open questions at the time
    • How a single receptor produces opposing pro/anti-fibrotic outcomes is unresolved
    • Direct coupling of RAMP1/CLR to YAP regulation not biochemically defined
  14. 2024 High

    Extended the CGRP-RAMP1 axis into immune-cancer and neuroimmune crosstalk, shaping commensal-specific T cells, endometriosis macrophages, and breast cancer invasion via cAMP/RhoC.

    Evidence Conditional RAMP1 KO, intravital imaging, RAMP1 KO macrophage co-cultures, pharmacological CGRP blockade, and microfluidic axon-cancer co-culture (some preprint)

    PMID:38451947 PMID:39196292 PMID:39504351 PMID:42079108

    Open questions at the time
    • Cell-type-specific signaling pathways incompletely mapped
    • Breast cancer and meningeal macrophage findings are preprint-stage
  15. 2025 Medium

    Connected RAMP1 to hormonal control of the CGRP system, showing estrogen upregulates Ramp1 and that RAMP1 is required for cyclical regulation of CGRP-system genes in the trigeminal ganglion.

    Evidence RT-qPCR across the estrous cycle in WT and Ramp1 KO mice with exogenous hormone administration and sex-stratified analysis

    PMID:40528180

    Open questions at the time
    • Direct estrogen-responsive elements in RAMP1 not mapped
    • Functional consequence for headache pathophysiology not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RAMP1 mechanistically directs opposing physiological outcomes (protective vs pathogenic) in different tissues, and how its ectodomain conformation couples to divergent intracellular effectors beyond cAMP, remains unresolved.
  • No experimental high-resolution structure of the human CLR/RAMP1 complex in the timeline
  • Tissue-specific effector selection (Gs/cAMP vs ERK vs YAP/Smad2) not mechanistically explained
  • Whether non-receptor RAMP1 functions exist independent of CLR is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 4 R-HSA-9609507 Protein localization 2
Partners
ARRB1CALCRLNKX3.1RAMP2RAMP3
Complex memberships
CGRP receptor (CLR/RAMP1 heterodimer)CLR/RAMP1/β-arrestin ternary complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 RAMP1 coexpression with the calcitonin receptor-like receptor (CRLR/CLR) converts it from an adrenomedullin receptor into a functional CGRP receptor; RAMP1 competes with RAMP2 for CRLR association, and RAMP1 expression inhibits RAMP2-evoked ADM receptor function while generating CGRP binding sites and CGRP-stimulated cAMP responses. Radioligand binding assays ([125I]hαCGRP, [125I]rADM) and CRE-luciferase cAMP reporter assays in transiently transfected COS-7 and UMR-106 cells with combinations of rCRLR, hRAMP1, and hRAMP2 Endocrinology High 10342881
2001 When expressed alone, RAMP1 is retained intracellularly in the ER and Golgi as a disulfide-linked homodimer; coexpression with CRLR redirects RAMP1 to the cell surface as a 1:1 heterodimer (without intermolecular disulfide bonds) and promotes intramolecular disulfide bond formation within RAMP1. CGRP activation leads to CRLR phosphorylation and dynamin- and β-arrestin-dependent endocytosis of a stable CRLR/RAMP1/β-arrestin ternary complex via clathrin-coated pits. Subcellular fractionation, co-immunoprecipitation, disulfide bond analysis, CGRP-stimulated internalization assays with dominant-negative dynamin and β-arrestin mutants in transfected cells The Journal of biological chemistry High 11535606
2007 CRLR and RAMP1 associate selectively to form heterodimers at the cell surface, as shown by BRET titration; both proteins can also form homodimers. RAMP1 is required for CRLR to engage G proteins and β-arrestin upon CGRP stimulation; a trafficking-deficient RAMP1 mutant still heterodimerizes with CRLR, indicating deficient surface targeting results from altered complex conformation rather than loss of heterodimerization. Bioluminescence resonance energy transfer (BRET) titration in living cells, radioligand binding, cAMP production assay, mutagenesis Biochemistry High 17503773
2006 The extracellular domain of RAMP1 adopts a three-helix structure with disulfide bonds at Cys27–Cys82, Cys40–Cys72, and Cys57–Cys104 (determined by site-directed mutagenesis); modeling identified Phe93, Tyr100, and Phe101 as a putative CLR-binding interface and Trp74/Phe92 as potential ligand interaction sites. Ab initio molecular modeling of RAMP1 extracellular domain, site-directed mutagenesis to map disulfide bonds Biophysical journal Medium 16632510
2009 Alanine mutagenesis of RAMP1 identified Tyr66 and His97 as critical for CLR trafficking to the cell surface (CLR recognition site), while Leu69 and Thr73 in helix 2 contribute to CGRP potency (CGRP recognition site); Met48 in helix 1 had only a modest effect on CLR surface expression. Alanine scanning mutagenesis of RAMP1 coexpressed with CLR in COS-7 cells; cell-surface ELISA and cAMP assays Biochemistry High 19072332
2009 Non-peptide CGRP receptor antagonists BIBN4096BS and MK-0974 interact with the CGRP receptor via Met42 of CLR and Trp74 of RAMP1; Trp74Lys mutation reduces BIBN4096BS affinity >300-fold and similarly reduces MK-0974 affinity, and Met42Ala reduces BIBN4096BS affinity 48-fold and MK-0974 affinity ~900-fold, placing the antagonist binding site at the CLR/RAMP1 extracellular domain interface. Site-directed mutagenesis of CLR residues 23–63 and RAMP1 Trp74, radioligand binding and functional assays in transfected cells Biochemical and biophysical research communications High 19914210
2010 Tryptophan-84 of RAMP1 is critical for both high-affinity non-peptide antagonist (telcagepant, BIBN4096BS) binding and agonist (CGRP and CGRP8-37) potency; Arg67 is important for telcagepant but not compound 3 (BIBN4096BS analog) binding, indicating distinct contact points for different antagonists within the RAMP1 N-terminal domain. Alanine replacement mutagenesis of RAMP1 residues, radioligand binding and cAMP assays in cells coexpressing CLR Biochemical and biophysical research communications High 20188075
2010 RAMP1-RAMP3 chimera analysis showed that helix 1 of RAMP1 and residues 62–69 in helix 2 are required for CLR trafficking; residues 86–89 of RAMP1 at the helix 2–3 junction are important for hαCGRP and adrenomedullin potency but not hβCGRP potency, suggesting a peptide-binding role; residues 90–94 have dual roles in CLR recognition and CGRP binding. RAMP1–RAMP3 chimera expression with CLR in COS-7 cells; cell-surface ELISA and cAMP assays Biochemistry Medium 20017504
2011 Position 74 of RAMP1 (Trp74) vs RAMP3 (Glu74) differentially affects adrenomedullin potency at the respective CLR complexes; geometry and charge at this residue contribute to differential AM pharmacology at AM2 and CGRP receptors, while CGRP and AM2/intermedin potency are largely unaffected by substitutions at this position in RAMP1. Site-directed mutagenesis of RAMP1 and RAMP3 at position 74 with multiple amino acid substitutions, coexpressed with CLR in COS-7 cells; cAMP assays and ELISA for surface expression Peptides Medium 21402116
2018 Photoaffinity cross-linking using unnatural amino acid mutagenesis in CLR ECL2 identified key contacts for CGRP within the transmembrane bundle: I284 in ECL2 and L291 at the top of TM5 are primary contacts; M223 in TM3 and F349 in TM6 are minor contacts. Molecular modeling indicates CGRP sits at the top of the TM bundle with Thr6 contacting H295 (important for activation) and Leu12/Ala13 contacting I284. Genetic code expansion and unnatural amino acid (p-azido-Phe) mutagenesis in CLR ECL2, photoaffinity cross-linking with fluorescein-CGRP analog, functional validation with [Leu16Ala]-CGRP analogue Biochemistry High 30004692
2013 NKX3.1 directly represses RAMP1 expression in prostate cells; multiple NKX3.1 binding sites were identified in the RAMP1 locus by ChIP-seq. RAMP1 knockdown reduces prostate cancer cell proliferation and tumorigenicity, associated with reduced MEK1 expression and decreased phospho-ERK1/2 levels, placing RAMP1 upstream of the MAPK signaling pathway in prostate cancer. ChIP-seq for NKX3.1 binding at RAMP1 locus, Nkx3.1 knockout mice analysis, shRNA knockdown of RAMP1 in prostate cancer cell lines with in vitro and in vivo tumorigenicity assays, gene expression profiling The American journal of pathology Medium 23867798
2014 RAMP1 deficiency in mice reduces antigen-induced airway hyperresponsiveness and lung inflammation in an ovalbumin asthma model; loss of CLR from smooth muscle cells specifically does NOT alter airway resistance, indicating CGRP/RAMP1 signaling drives asthma pathology via endothelial and inflammatory cells rather than smooth muscle cells. RAMP1 knockout mice (exon 3 excision) and smooth-muscle-specific CLR heterozygous mice subjected to ovalbumin sensitization/challenge; airway resistance (methacholine challenge) and inflammatory cell measurements PloS one Medium 25010197
2012 RAMP1 deficiency improves bacterial clearance in the early phase of polymicrobial septic peritonitis by reducing IL-10-mediated immunosuppression; CGRP directly increases IL-10 production in macrophages via RAMP1 signaling in response to LPS, and RAMP1 deficiency increases neutrophil recruitment and defensin-α1 release. RAMP1 KO mice in cecal ligation and puncture model; cytokine measurements in plasma and peritoneal lavage, in vitro CGRP stimulation of macrophages, neutrophil and defensin assays Immunobiology Medium 22656887
2019 RAMP1 mediates amylin's anorectic signaling: RAMP1/3 double KO mice are insensitive to both amylin and salmon calcitonin (sCT) food intake suppression; RAMP1 single KO mice respond to amylin but not sCT, while RAMP3 KO mice respond to sCT but not amylin. RAMP1 is also required for normal fat utilization and meal pattern regulation. RAMP1, RAMP3, and RAMP1/3 global KO mice; acute intraperitoneal amylin/sCT injection food intake assays, metabolic measurements, meal pattern analysis Neuroscience Medium 31881259
2019 RAMP1 signaling in CD4+ T cells promotes inflammation-associated lymphangiogenesis by driving VEGF-C and VEGF-D expression; RAMP1-deficient mice show suppressed LPS-induced lymphangiogenesis, reduced CD4+ cell numbers, and a shift toward pro-inflammatory (M1) macrophage phenotype with increased CD11b+ cells. RAMP1 KO mice with LPS-induced peritoneal inflammation model; FITC-dextran lymphatic flow assay, immunostaining for CD4+/CD11b+ cells, VEGF-C/D expression analysis, CD4+ cell depletion experiments Laboratory investigation Medium 31911634
2017 RAMP1 signaling promotes lymphangiogenesis during secondary lymphedema by supporting VEGF-C/VEGFR3 expression and reparative macrophage polarization; RAMP1-deficient mice show sustained tail lymphedema, suppressed lymphangiogenesis, dilated/dysfunctional lymphatics, and elevated M1 macrophage gene expression (TNF-α, IL-1β) with decreased M2 markers (IL-10). RAMP1 KO mice in surgical tail lymphedema model; tail diameter measurements, VEGF-C/VEGFR3 expression, macrophage marker analysis The Journal of surgical research Medium 29078910
2020 RAMP1 deficiency severely impairs liver regeneration after partial hepatectomy and carbon tetrachloride injury; mechanistically, RAMP1 loss leads to hyperphosphorylation of YAP at Ser127 and Ser397, reducing YAP/TAZ protein levels and expression of YAP-controlled cell cycle regulators. In vitro, CGRP treatment of liver slice cultures and primary human hepatocytes increases YAP protein and reduces YAP phosphorylation. RAMP1 KO mice subjected to 70% partial hepatectomy and CCl4 model; liver mass recovery, hepatocyte proliferation (Ki67), YAP/TAZ protein levels and phosphorylation (Western blot), ex vivo CGRP treatment of liver slices and primary hepatocytes FASEB journal High 32329113
2022 RAMP1 is C-mannosylated at Trp56 (identified by mass spectrometry); C-mannosylation enhances RAMP1 protein stability and promotes cell migration activity but does not affect RAMP1 plasma membrane trafficking or its function in transporting CRLR to the cell surface. Mass spectrometry to identify C-mannosylation site, C-mannosylation-deficient RAMP1 mutants, protein stability assays, cell migration assays The FEBS journal Medium 35942636
2022 RAMP1 is expressed on intestinal goblet cells in mice and humans; nociceptor (Nav1.8+CGRP+) signaling via the CGRP-RAMP1 pathway induces rapid goblet cell emptying and mucus secretion. Loss of epithelial Ramp1 increases susceptibility to colitis; CGRP administration protects nociceptor-ablated mice against colitis. RAMP1 cell-specific KO (epithelial), nociceptor ablation, chemogenetic nociceptor activation, capsaicin treatment, mouse colitis model (DSS), CGRP administration rescue experiments; histology, mucus thickness measurement Cell High 36243004
2024 The CGRP-RAMP1 axis in skin mediates direct neuroimmune communication: commensal colonization upregulates RAMP1 on CD8+ T lymphocytes; CGRP-RAMP1 signaling in commensal-specific T cells constrains Type 17 responses and moderates the activation status of microbiota-reactive lymphocytes, shaping the overall skin epithelial activation state and wound healing responses. Intravital imaging of T cell proximity to nerve fibers, flow cytometry of RAMP1+ T cells after commensal colonization, RAMP1 conditional KO in T cells, wound healing assays, commensal-specific T cell transfer experiments Proceedings of the National Academy of Sciences of the United States of America High 38451947
2024 CGRP/RAMP1 signaling in macrophages drives endometriosis lesion growth and pain: CGRP stimulation changes macrophage phenotype toward a pro-endometriosis state with impaired efferocytosis and support of endometrial cell growth in a RAMP1-dependent manner. FDA-approved CGRP-RAMP1 blockers reduce mechanical hyperalgesia, spontaneous pain, and lesion size in mice. Nonsurgical mouse endometriosis model, nociceptor ablation, in vitro CGRP-stimulated macrophage co-culture with endometrial cells (RAMP1 KO macrophages as controls), efferocytosis assays, pharmacological CGRP blockade Science translational medicine High 39504351
2024 CGRP-RAMP1 signaling promotes liver fibrosis via TGFβ1/Smad2 and YAP pathways: RAMP1 deficiency attenuates fibrogenesis and hepatic stellate cell (HSC) activity. In LX-2 HSC cells, CGRP induces TGFβ1 production and downstream Smad2 signaling, increases α-SMA expression and collagen synthesis, and promotes YAP activation and nuclear translocation downstream of TGFβ1/Smad2. RAMP1 KO mice in liver fibrosis model; in vitro CGRP stimulation of LX-2 cells; Western blot for Smad2 phosphorylation, α-SMA, collagen, YAP nuclear translocation Experimental cell research Medium 39103072
2024 RAMP1 protects against hepatic ischemia-reperfusion injury by inhibiting ERK/MAPK activation and YAP phosphorylation; RAMP1 KO mice show increased apoptosis and liver damage associated with elevated ERK and YAP phosphorylation, and ERK or YAP inhibitors reduce apoptosis in RAMP1 KO livers. RAMP1 KO mice in 70% liver ischemia-reperfusion model; histology, serum transaminase, ERK/YAP phosphorylation (Western blot), pharmacological rescue with SCH772984 (ERK inhibitor) and PY-60 (YAP inhibitor) Journal of clinical and translational hepatology Medium 38638379
2024 In dental pulp, CGRP released from sensory nerves binds RAMP1 on dental pulp stem cells (DPSCs) to promote collective cell migration to injury sites; sensory denervation impairs DPSC recruitment and pulp repair. Single-cell RNA-seq identified the CGRP-Ramp1 axis as the communication mechanism; BIBN4096 (CGRP receptor antagonist) blocks the pro-migratory effect. Sensory denervation model, indirect co-culture of DPSCs with trigeminal neurons, CGRP recombinant protein and BIBN4096 antagonist treatment, single-cell RNA-seq, immunohistochemistry, migration assays Cellular and molecular life sciences Medium 39196292
2018 RAMP1 expressed on Kupffer cells (KCs) is a critical regulator of immune-mediated hepatitis: RAMP1 KO mice show severe ConA-induced liver injury with increased inflammatory cytokines; KC depletion ameliorates damage; co-culture of KCs with splenic T cells increases cytokine expression from both cell types in a RAMP1-dependent manner. Adoptive transfer of RAMP1-deficient splenic T cells causes a modest increase in liver injury. RAMP1 KO mice in ConA hepatitis model; KC depletion, splenectomy, T cell depletion, adoptive transfer of splenic T cells, KC/T cell co-culture with cytokine measurements PloS one Medium 30462657
2019 CGRP/CRLR/RAMP1 signaling in hematopoietic progenitor cells is required for stress-induced hematopoiesis: Ramp1-deficient bone marrow cells have decreased repopulation capacity and increased ROS production and apoptosis under proliferative stress, while steady-state hematopoiesis is maintained. Continuous CGRP exposure reduces immature hematopoietic and differentiated myeloid cells in vivo. Ramp1 KO mice, BM transplantation/repopulation assays, ROS and apoptosis measurements in transplanted BM cells, continuous CGRP infusion in vivo Scientific reports Medium 30674976
2025 Ramp1 expression in the trigeminal ganglion (TG) varies across the estrous cycle (peaking in proestrus) in inverse correlation with Calca (CGRPα); Ramp1 expression correlates with Esr2 (ERβ), and estrogen treatment upregulates Ramp1. In Ramp1 KO mice, the cyclical variation of Calca, Ramp2, and Ramp3 seen in WT is absent, and basal Calca is elevated in males, establishing RAMP1 as essential for hormonal regulation of the CGRP system in the TG. RT-qPCR across estrous cycle stages in WT and Ramp1 KO mice, exogenous estrogen/progesterone administration, sex-stratified analysis The journal of headache and pain Medium 40528180
2024 CGRP-RAMP1 signaling mediates a subset of meningeal macrophage calcium responses to cortical spreading depolarization (CSD): CGRP/RAMP1 signaling mediates the increase (but not the decrease) in CSD-mediated Ca2+ signaling in meningeal macrophages in vivo. Intravital two-photon calcium imaging in awake Pf4Cre:TIGRE2.0-GCaMP6s reporter mice; CGRP/RAMP1 pharmacological manipulation during CSD bioRxivpreprint Low bio_10.1101_2025.10.01.679335
2026 Sensory neurons inhibit breast cancer cell invadopodia and metastasis via direct CGRP signaling through the CRLR/RAMP1 complex on cancer cells; CGRP induces rapid intracellular cAMP increases and subsequent RhoC activation in cancer cells, suppressing invadopodia assembly and ECM degradation. Loss of RAMP1 function enhances 3D spheroid invasion and in vivo lung metastasis. Invasive breast cancer subtypes show progressively decreased RAMP1/CRLR expression. Microfluidic device (DACIT) for axon-cancer cell co-culture, CGRP treatment with CRLR/RAMP1 knockdown, intracellular cAMP and RhoC activity assays, 3D spheroid invasion assays, in vivo metastasis experiments, in silico RNAseq and patient sample analysis bioRxivpreprint Medium 42079108
2005 CGRP exerts antiapoptotic effects in H9c2 cardiomyoblasts under oxidative stress specifically through the RAMP1/CRLR complex: CGRP pretreatment inhibits phosphatidylserine externalization, caspase-3 activation, and DNA fragmentation induced by H2O2, increases Bcl-2 and prevents Bax increase; CGRP(8-37) (RAMP1/2 inhibitor) abolishes protection, while adrenomedullin (RAMP2 agonist) does not protect, pinpointing RAMP1/CRLR as the mediating complex. MTT cell viability assay, annexin V staining, caspase-3 activity, DNA fragmentation, RT-PCR for RAMP isoforms, dot blot for Bcl-2/Bax, pharmacological dissection with CGRP8-37 and ADM in H9c2 cells Journal of molecular and cellular cardiology Medium 16242145
2013 RAMP1 overexpression in MG-63 osteoblast-like cells promotes CRLR surface localization and enhances CGRP-mediated osteogenic differentiation, including increased collagen I expression, alkaline phosphatase activity, and mineral deposition (Alizarin Red staining), indicating RAMP1 quantity directly modulates CGRP receptor surface expression and downstream osteogenic signaling. Stable RAMP1 transfection in MG-63 cells, Western blot and RT-PCR for RAMP1/CRLR expression, immunofluorescence for CRLR distribution, ALP activity assay, Alizarin Red mineralization staining Journal of cellular biochemistry Medium 22949393
2024 CGRP-RAMP1 signaling activates p38 MAPK in osteoblasts during mechanical stimulation; low-magnitude compressive force upregulates RAMP1 expression and phosphorylates p38, and CGRP treatment similarly upregulates RAMP1 and p38 phosphorylation with increased osteogenic markers RUNX2 and osteocalcin, suggesting RAMP1 acts upstream of p38 in osteogenic differentiation. Osteoblast compressive force model, CGRP treatment, Western blot for RAMP1, RUNX2, osteocalcin, p38, and p-p38; Alizarin Red staining Journal of orthopaedic surgery and research Low 38825686
2025 In vitiligo, oxidative stress impairs Treg expansion via dysregulated CGRP-RAMP1-Gαi3 signaling: RAMP1+ Tregs are increased in active vitiligo; H2O2 and CGRP upregulate Gαi3 while suppressing p-CREB and PCNA in Treg-like cells, impairing proliferation. CGRP injection exacerbates depigmentation in a mouse vitiligo model. Flow cytometry of CLA+ Tregs from patients, in vitro CGRP/H2O2 stimulation of MT-2 cells with Western blot for Gαi3, p-CREB, PCNA; intradermal CGRP injection in mouse vitiligo model Free radical biology & medicine Low 41453541

Source papers

Stage 0 corpus · 63 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and calcitonin gene-related peptide (CGRP) immunoreactivity in the rat trigeminovascular system: differences between peripheral and central CGRP receptor distribution. The Journal of comparative neurology 268 18186028
2022 Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection. Cell 194 36243004
1999 A receptor activity modifying protein (RAMP)2-dependent adrenomedullin receptor is a calcitonin gene-related peptide receptor when coexpressed with human RAMP1. Endocrinology 142 10342881
2001 Agonist-promoted internalization of a ternary complex between calcitonin receptor-like receptor, receptor activity-modifying protein 1 (RAMP1), and beta-arrestin. The Journal of biological chemistry 114 11535606
2025 Nociceptive neurons promote gastric tumour progression via a CGRP-RAMP1 axis. Nature 84 39972142
2010 Cerebellar distribution of calcitonin gene-related peptide (CGRP) and its receptor components calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) in rat. Molecular and cellular neurosciences 66 21040789
2002 Increased myocardial expression of RAMP1 and RAMP3 in rats with chronic heart failure. Biochemical and biophysical research communications 55 12051717
2005 Antiapoptotic effect of calcitonin gene-related peptide on oxidative stress-induced injury in H9c2 cardiomyocytes via the RAMP1/CRLR complex. Journal of molecular and cellular cardiology 51 16242145
2014 Deficiency of RAMP1 attenuates antigen-induced airway hyperresponsiveness in mice. PloS one 41 25010197
2000 Dexamethasone increases RAMP1 and CRLR mRNA expressions in human vascular smooth muscle cells. Biochemical and biophysical research communications 40 10772950
2007 Assembly and signaling of CRLR and RAMP1 complexes assessed by BRET. Biochemistry 38 17503773
2012 Deficiency of the CGRP receptor component RAMP1 attenuates immunosuppression during the early phase of septic peritonitis. Immunobiology 37 22656887
2019 RAMP1 and RAMP3 Differentially Control Amylin's Effects on Food Intake, Glucose and Energy Balance in Male and Female Mice. Neuroscience 36 31881259
2020 RAMP1 signaling in immune cells regulates inflammation-associated lymphangiogenesis. Laboratory investigation; a journal of technical methods and pathology 35 31911634
2009 Non-peptidic antagonists of the CGRP receptor, BIBN4096BS and MK-0974, interact with the calcitonin receptor-like receptor via methionine-42 and RAMP1 via tryptophan-74. Biochemical and biophysical research communications 35 19914210
2024 The neuroimmune CGRP-RAMP1 axis tunes cutaneous adaptive immunity to the microbiota. Proceedings of the National Academy of Sciences of the United States of America 34 38451947
2010 Mapping the CGRP receptor ligand binding domain: tryptophan-84 of RAMP1 is critical for agonist and antagonist binding. Biochemical and biophysical research communications 34 20188075
2015 DNA methylation of RAMP1 gene in migraine: an exploratory analysis. The journal of headache and pain 33 26501962
2024 Nociceptor-to-macrophage communication through CGRP/RAMP1 signaling drives endometriosis-associated pain and lesion growth in mice. Science translational medicine 31 39504351
2012 Localization of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) in human gastrointestinal tract. Peptides 29 22484227
2017 RAMP1 signaling improves lymphedema and promotes lymphangiogenesis in mice. The Journal of surgical research 27 29078910
2019 Targeting the CALCB/RAMP1 axis inhibits growth of Ewing sarcoma. Cell death & disease 26 30741933
2017 RAMP1 suppresses mucosal injury from dextran sodium sulfate-induced colitis in mice. Journal of gastroenterology and hepatology 24 27513455
2020 The CGRP receptor component RAMP1 links sensory innervation with YAP activity in the regenerating liver. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23 32329113
2017 Distribution of CGRP and its receptor components CLR and RAMP1 in the rat retina. Experimental eye research 23 28603014
2013 RAMP1 is a direct NKX3.1 target gene up-regulated in prostate cancer that promotes tumorigenesis. The American journal of pathology 23 23867798
2010 Involvement of vascular endothelial growth factor signaling in CLR/RAMP1 and CLR/RAMP2-mediated pro-angiogenic effect of intermedin on human vascular endothelial cells. International journal of molecular medicine 23 20596610
2009 Structure-function analysis of RAMP1 by alanine mutagenesis. Biochemistry 23 19072332
2011 Structure-function analysis of amino acid 74 of human RAMP1 and RAMP3 and its role in peptide interactions with adrenomedullin and calcitonin gene-related peptide receptors. Peptides 22 21402116
2018 Photoaffinity Cross-Linking and Unnatural Amino Acid Mutagenesis Reveal Insights into Calcitonin Gene-Related Peptide Binding to the Calcitonin Receptor-like Receptor/Receptor Activity-Modifying Protein 1 (CLR/RAMP1) Complex. Biochemistry 20 30004692
2012 Association study of the calcitonin gene-related polypeptide-alpha (CALCA) and the receptor activity modifying 1 (RAMP1) genes with migraine. Gene 20 23237777
2018 RAMP1 in Kupffer cells is a critical regulator in immune-mediated hepatitis. PloS one 18 30462657
2015 Association of RAMP1 rs7590387 with the risk of migraine transformation into medication overuse headache. Headache 17 25881990
2006 Aldosterone increases RAMP1 expression in mesenteric arteries from spontaneously hypertensive rats. Regulatory peptides 17 16458982
2006 Characterization of the structure of RAMP1 by mutagenesis and molecular modeling. Biophysical journal 16 16632510
2019 CGRP-CRLR/RAMP1 signal is important for stress-induced hematopoiesis. Scientific reports 15 30674976
2021 Differential Synovial CGRP/RAMP1 Expression in Men and Women With Knee Osteoarthritis. Cureus 14 34109089
2013 The influence of RAMP1 overexpression on CGRP-induced osteogenic differentiation in MG-63 cells in vitro: an experimental study. Journal of cellular biochemistry 14 22949393
2025 RAMP1-dependent hormonal regulation of CGRP and its receptor in the trigeminal ganglion. The journal of headache and pain 12 40528180
2023 Body weight lowering effect of glucose-dependent insulinotropic polypeptide and glucagon-like peptide receptor agonists is more efficient in RAMP1/3 KO than in WT mice. European journal of pharmacology 11 37454968
2022 Characterization of Antibodies against Receptor Activity-Modifying Protein 1 (RAMP1): A Cautionary Tale. International journal of molecular sciences 10 36555690
2024 Deletion of RAMP1 Signaling Enhances Diet-induced Obesity and Fat Absorption via Intestinal Lacteals in Mice. In vivo (Athens, Greece) 9 38148085
2019 The neuropeptide receptor subunit RAMP1 constrains the innate immune response during acute pancreatitis in mice. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 9 31109903
2011 Suppression of ovalbumin-induced allergic diarrhea by diminished intestinal peristalsis in RAMP1-deficient mice. Biochemical and biophysical research communications 9 21683059
2024 RAMP1 Signaling Mitigates Acute Lung Injury by Distinctively Regulating Alveolar and Monocyte-Derived Macrophages. International journal of molecular sciences 8 39337592
2022 A High Methylation Level of a Novel -284 bp CpG Island in the RAMP1 Gene Promoter Is Potentially Associated with Migraine in Women. Brain sciences 7 35624913
2021 Molecular simulations reveal the impact of RAMP1 on ligand binding and dynamics of calcitonin gene-related peptide receptor (CGRPR) heterodimer. Computers in biology and medicine 7 34923287
2010 Structure-function analysis of RAMP1-RAMP3 chimeras. Biochemistry 6 20017504
2024 Sensory nerves drive migration of dental pulp stem cells via the CGRP-Ramp1 axis in pulp repair. Cellular and molecular life sciences : CMLS 5 39196292
2023 The neuroimmune CGRP-RAMP1 axis tunes cutaneous adaptive immunity to the microbiota. bioRxiv : the preprint server for biology 5 38234748
2022 C-mannosylation regulates stabilization of RAMP1 protein and RAMP1-mediated cell migration. The FEBS journal 5 35942636
2024 Signalling of the neuropeptide calcitonin gene-related peptide (CGRP) through RAMP1 promotes liver fibrosis via TGFβ1/Smad2 and YAP pathways. Experimental cell research 4 39103072
2025 Sensory neuropeptide CGRP and its co-receptor RAMP1 drive tumour cell growth in gastrointestinal cancers. BMJ oncology 3 41158750
2024 Involvement of RAMP1/p38MAPK signaling pathway in osteoblast differentiation in response to mechanical stimulation: a preliminary study. Journal of orthopaedic surgery and research 3 38825686
2025 Oxidative stress impairs the expansion of regulatory T cells in active vitiligo via dysregulated CGRP-RAMP1-Gαi3 signaling. Free radical biology & medicine 2 41453541
2024 Nociceptive neurons interact directly with gastric cancer cells via a CGRP/Ramp1 axis to promote tumor progression. bioRxiv : the preprint server for biology 2 38496544
2024 RAMP1 Protects Hepatocytes against Ischemia-reperfusion Injury by Inhibiting the ERK/YAP Pathway. Journal of clinical and translational hepatology 2 38638379
2025 Intra-tumoural RAMP1+ B cells promote resistance to neoadjuvant anti-PD-1-based therapy in oesophageal squamous cell carcinoma. Immunotherapy advances 1 40385640
2025 Acupuncture accelerates wound healing via CGRP-RAMP1-TSP1-mediated macrophage M2 polarization. Chinese medicine 1 41250153
2024 Spinal RAMP1-mediated neuropathic pain sensitisation in the aged mice through the modulation of CGRP-CRLR pain signalling. Heliyon 1 39224276
2026 Neuroinflammation and RAMP1: the Role of the Peripheral and Central Nervous System in Tumor Progression. Cell biochemistry and biophysics 0 41649670
2026 Sensory neurons inhibit invadopodia and metastasis via direct CGRP-RAMP1-cAMP signaling to cancer cells. bioRxiv : the preprint server for biology 0 42079108
2024 Lack of RAMP1 Signaling Suppresses Liver Regeneration and Angiogenesis Following Partial Hepatectomy in Mice. In vivo (Athens, Greece) 0 39187322

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