Affinage

RAMP2

Receptor activity-modifying protein 2 · UniProt O60895

Length
175 aa
Mass
19.6 kDa
Annotated
2026-06-10
44 papers in source corpus 29 papers cited in narrative 29 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

RAMP2 is a single-pass transmembrane accessory protein that defines G protein-coupled receptor pharmacology and is essential for vascular integrity (PMID:10217420, PMID:18097473). Its canonical role is to obligatorily partner with calcitonin receptor-like receptor (CRLR/CL) to constitute a high-affinity adrenomedullin (AM) receptor that signals through cAMP, with residues 86–92 of its extracellular N-terminal domain critical for AM binding (PMID:10217420, PMID:11591721); this CL/RAMP2 receptor is pharmacologically distinct from the CL/RAMP3 receptor, conferring AM22-52 selectivity (PMID:12970090). In the endothelium, the AM-RAMP2 system is indispensable for vascular development and barrier integrity: its loss is embryonic lethal with vascular fragility, hemorrhage, and endothelial detachment, while its mechanism of action involves control of the Rac1-GTP/RhoA-GTP balance, cortical actin organization, and tight-junction stability (PMID:18097473, PMID:23355623). Loss of endothelial RAMP2 produces vascular leakage, endothelial-mesenchymal transition-like changes, organ fibrosis, and pre-metastatic niche formation, whereas its activity supports angiogenesis, re-endothelialization, and barrier protection across retinal, hepatic, renal, and pulmonary contexts (PMID:23355623, PMID:23562442, PMID:27307317, PMID:28324104). Beyond the AM/CL axis, RAMP2 broadly tunes class B GPCR signaling: it acts as a negative allosteric modulator of the glucagon receptor by disordering its extracellular domain to suppress active-state signaling and by rerouting receptor trafficking and G protein/β-arrestin coupling (PMID:37001505, PMID:34271220), and it shifts PTH1R into a preactivated state with altered Gi3 and β-arrestin2 coupling (PMID:35914163). Human RAMP2 pathogenic variants disrupt AM-RAMP2/CRLR-cAMP signaling and cause mutant protein aggregation, linking RAMP2 dysfunction to retinal ganglion cell death (PMID:31000793).

Mechanistic history

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

    Established RAMP2's defining molecular function—that it is not itself a receptor but an obligate accessory subunit that, together with CRLR, builds a functional high-affinity adrenomedullin receptor in vascular cells.

    Evidence Heterologous co-expression in HeLa/293 EBNA cells with cAMP functional readout and RT-PCR

    PMID:10217420

    Open questions at the time
    • Did not map the RAMP2 residues responsible for AM binding
    • Stoichiometry and structure of the CRLR/RAMP2 complex unresolved
  2. 2001 High

    Localized the binding determinant within RAMP2, showing its extracellular N-terminal residues 86–92 are required for AM binding and signaling independent of complex surface expression.

    Evidence RAMP chimeras/deletion mutants with CRLR in HEK293, 125I-AM radioligand binding, cAMP and CRE-luciferase reporter assays in cardiomyocytes

    PMID:11591721 PMID:11754972

    Open questions at the time
    • Atomic-resolution contact map between residues 86–92 and AM not defined
    • Role of CRLR residues in cooperative binding not addressed
  3. 2003 High

    Demonstrated that RAMP identity dictates receptor pharmacology, distinguishing CL/RAMP2 from CL/RAMP3 by differential antagonist selectivity and establishing RAMPs as pharmacological switches.

    Evidence Transient and endogenous expression in COS-7, Rat 2, L6 cells with cAMP assays and multiple receptor antagonists

    PMID:12970090

    Open questions at the time
    • Structural basis for the pharmacological divergence not determined
    • Species-combination effects complicate human extrapolation
  4. 2008 High

    Proved RAMP2 is genetically essential for vascular development in vivo, with knockout phenocopying AM loss and establishing an allele-dose-dependent role in vascular integrity.

    Evidence Global and heterozygous RAMP2 knockout mice, EC overexpression, histology, vascular permeability and tight-junction assays

    PMID:18097473

    Open questions at the time
    • Embryonic lethality precluded analysis of adult/tissue-specific roles
    • Downstream signaling mediating integrity not yet defined
  5. 2013 High

    Defined the intracellular mechanism by which endothelial RAMP2 maintains vascular integrity—control of the Rac1-GTP/RhoA-GTP ratio and cortical actin—using cell-type-specific and inducible knockouts.

    Evidence Endothelial-specific and drug-inducible RAMP2 KO mice, Rac1/RhoA GTP measurement, actin imaging, permeability and histopathology; OIR retinal model

    PMID:23355623 PMID:23562442

    Open questions at the time
    • How AM-RAMP2-cAMP signaling links to Rac1/RhoA GTPase regulation mechanistically unresolved
    • Effector linking signaling to actin remodeling not identified
  6. 2016 High

    Extended endothelial RAMP2 function to disease processes, showing its loss promotes EndMT, pre-metastatic niche formation, and tumor metastasis, defining a vasoprotective tumor-suppressive role.

    Evidence Inducible EC-specific KO and gain-of-function mice, tumor metastasis models, S100A8/9 and SAA3 marker staining; vascular injury and progenitor cell assays

    PMID:27307317 PMID:28324104

    Open questions at the time
    • Causal chain from barrier loss to chemokine induction not fully dissected
    • Whether RAMP2 acts cell-autonomously in metastatic niche cells unclear
  7. 2014 High

    Broadened RAMP2's physiological reach beyond vasculature—to reproduction, pituitary/skeletal homeostasis, renal ER-stress protection, and hepatic endothelial differentiation—via PERK-CHOP suppression and other pathways.

    Evidence RAMP2+/- mice with reproductive, prolactin, bone-density phenotyping; tunicamycin renal injury with PERK/CHOP Westerns; embryoid body LSEC differentiation

    PMID:21566080 PMID:21782867 PMID:24505304

    Open questions at the time
    • Whether these effects all proceed through AM/CL or via other partner receptors unresolved
    • Tissue-specific receptor partners not all defined
  8. 2017 High

    Revealed RAMP2 as a broad modulator of class B GPCRs beyond AM/CL, showing it remodels glucagon receptor pharmacology, surface expression, trafficking, and G protein/β-arrestin coupling.

    Evidence Yeast and mammalian functional assays, confocal colocalization, cell-surface ELISA, competition binding, NanoBiT, WASH-KO MEFs, hepatic AAV in mice

    PMID:26198634 PMID:28586439 PMID:34271220

    Open questions at the time
    • Whether endogenous RAMP2/GCGR co-expression occurs at physiologically relevant levels not established in these studies
    • Structural basis of GCGR modulation not yet defined here
  9. 2019 High

    Connected RAMP2 to human disease, identifying pathogenic variants that aggregate and disrupt AM-RAMP2/CRLR-cAMP signaling, with retinal ganglion cell death in a mouse model.

    Evidence Exome/Sanger sequencing, heterologous mutant expression, aggregation imaging, cAMP measurement, heterozygous Ramp2 KO retinal histology

    PMID:31000793

    Open questions at the time
    • Mechanism linking cAMP reduction to ganglion cell death not detailed
    • Genotype-phenotype relationships across variants not fully resolved
  10. 2019 Medium

    Identified a regulatory interaction with CRF receptors, showing CRFR1 (not CRFR2) controls RAMP2 cell-surface expression in a ligand-dependent manner.

    Evidence Co-expression in four cell lines, cell-surface ELISA for FLAG-RAMP2, RT-PCR, molecular modelling, CRF pre-treatment

    PMID:30826286

    Open questions at the time
    • No direct binding assay confirming physical interaction
    • Functional consequence of CRFR1-RAMP2 trafficking not established
  11. 2022 High

    Demonstrated RAMP2 allosterically primes PTH1R into a preactivated state with agonist-dependent rewiring of Gi3 and β-arrestin2 coupling, generalizing its allosteric-modulator role.

    Evidence Optical biosensors of PTH1R activation/signaling with RAMP2 co-expression and homology modelling

    PMID:35914163

    Open questions at the time
    • Structural model is homology-based, not experimentally solved
    • Physiological context of PTH1R-RAMP2 co-expression not addressed
  12. 2023 High

    Provided the structural mechanism of RAMP2's negative allosteric modulation of GCGR—disordering the ECD and TM6 to inhibit active states—resolving how RAMP2 broadly suppresses downstream signaling.

    Evidence Cryo-EM (2.9 Å) of GCGR-Gs with RAMP2, HDX-MS, smFRET, downstream signaling assays

    PMID:37001505

    Open questions at the time
    • Whether the same conformational mechanism applies to PTH1R/CRFR modulation untested
    • In vivo relevance of GCGR-RAMP2 antagonism in metabolic physiology not established here
  13. 2023 Medium

    Showed RAMP2 in non-endothelial cells (hepatocytes) drives angiogenic regeneration via a PEDF-to-VEGFA switch, expanding its angiogenic role to a paracrine context.

    Evidence AAV gene manipulation in Alb-Cre-CRISPR/Cas9 mice, hepatectomy/ALPPS models, organoids, PEDF/VEGFA measurement

    PMID:37918568

    Open questions at the time
    • Receptor partner mediating hepatocyte RAMP2 signaling not defined
    • Direct molecular link from RAMP2 to PEDF/VEGFA switch unclear
  14. 2021 High

    Defined a cardiomyocyte-autonomous role for RAMP2 in mitochondrial homeostasis required for adaptation to cardiac stress.

    Evidence Cardiomyocyte-specific RAMP2 KO mice with TAC, echocardiography, pressure-volume, mitochondrial membrane potential and respiration assays

    PMID:33545715

    Open questions at the time
    • Molecular link between RAMP2 signaling and mitochondrial function not identified
    • Whether this requires AM/CL signaling not established
  15. 2025 Medium

    Reinforced the AM-RAMP2 system as a pulmonary endothelial barrier and anti-inflammatory regulator, acting via Epac1 and synergizing with shear stress to maintain homeostatic and anti-coagulation programs.

    Evidence DI-E-RAMP2-/- and RAMP3-/- LPS/ARDS models, ECIS/XperT barrier assays under shear stress, pharmacological RAMP2 blockade, marker expression; EAU immunomodulation models

    PMID:38012983 PMID:40465267 PMID:41597226

    Open questions at the time
    • Direct signaling chain from AM-RAMP2 to Epac1 induction not dissected
    • RAMP3 compensation complicates attribution of specific effects

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RAMP2 mechanistically couples its receptor-modulating activity to downstream cytoskeletal (Rac1/RhoA), mitochondrial, and barrier programs across distinct cell types remains unresolved.
  • No unifying signaling intermediary linking AM-RAMP2-cAMP to actin/mitochondrial outcomes
  • Cell-type-specific receptor partners for non-CL functions incompletely mapped
  • No experimental structure of the CRLR/RAMP2-AM receptor complex in the timeline

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0060089 molecular transducer activity 3 GO:0005198 structural molecule activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-9609507 Protein localization 3
Partners
ADMCALCRLCRHR1GCGRPTH1R
Complex memberships
CRLR/RAMP2 adrenomedullin receptor

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 RAMP2 forms a functional complex with calcitonin receptor-like receptor (CRLR) to constitute a high-affinity adrenomedullin receptor that mediates cAMP elevation in human endothelial and vascular smooth muscle cells; RAMP2 but not RAMP1 or RAMP3 mRNA was detected in these cells. Heterologous co-expression in HeLa EBNA and 293 EBNA cells, cAMP functional assay, RT-PCR FEBS letters High 10217420
2001 Residues 86–92 of RAMP2 extracellular N-terminal domain are critical for high-affinity 125I-AM binding and AM-evoked cAMP production at the CRLR/RAMP2 receptor heterodimer; deletion of these seven residues significantly attenuates AM binding without impairing cell surface expression of the complex. RAMP chimeras and deletion mutants co-expressed with CRLR in HEK293 cells; 125I-AM radioligand binding; cAMP production assay; alanine scanning mutagenesis The Journal of biological chemistry High 11591721
2001 In rat cardiomyocytes, CRLR and RAMP2 together constitute a functional AM receptor; overexpression of RAMP2 and CRLR additively potentiated AM-induced CRE-luciferase (cAMP-responsive) signaling approximately 4-fold over control; AM signaling was abolished by CGRP8-37 antagonist or CRLR antisense. Transient transfection of neonatal cardiomyocytes with CRE-luciferase reporter; CGRP8-37 antagonist; CRLR antisense; RT-PCR Peptides Medium 11754972
2003 CL/RAMP2 and CL/RAMP3 produce pharmacologically distinct AM receptors: AM22-52 shows selectivity for CL/RAMP2 over CL/RAMP3, whereas CGRP8-37 shows the opposite selectivity in mixed species combinations; BIBN4096BS does not antagonise AM at either receptor. Transient expression in COS-7 cells and endogenous expression in Rat 2 and L6 cells; cAMP functional assays with receptor antagonists; apparent pA2 determination British journal of pharmacology High 12970090
2004 AM promotes HUVEC migration, invasion, and differentiation into cord-like structures on Matrigel via CRLR/RAMP2 (and CRLR/RAMP3) receptors; AM-induced capillary tube formation is not blocked by anti-VEGF antibodies, indicating AM does not act indirectly through VEGF upregulation. Migration and invasion assays, Matrigel tube formation, receptor blocking antibodies, anti-VEGF antibody neutralization in HUVECs International journal of cancer Medium 14712479
2006 siRNA-mediated knockdown of RAMP2 in HUVECs (~60% reduction in mRNA) decreased capillary-like tube formation in response to AM on Matrigel, establishing RAMP2 as required for AM-driven angiogenesis in endothelial cells. siRNA transfection in HUVECs; RT-PCR quantification of RAMP2 mRNA; Matrigel tube formation assay International journal of molecular medicine Medium 16964401
2008 RAMP2 is essential for vascular integrity and angiogenesis in vivo: RAMP2-/- embryos die at midgestation with vascular fragility, severe edema, hemorrhage, and deformed ECs detached from basement membrane, phenocopying AM-/- embryos. RAMP2+/- adults show vascular hyperpermeability and impaired neovascularization. EC overexpressing RAMP2 show enhanced capillary formation, firmer tight junctions, and reduced vascular permeability. Global RAMP2 knockout mice; heterozygous mice; EC overexpression; histology; vascular permeability assays; tight junction marker expression The Journal of clinical investigation High 18097473
2010 Intermedin mediates pro-angiogenic effects on HUVECs via CLR/RAMP1 and CLR/RAMP2 complexes (but not CLR/RAMP3); this involves both VEGF mRNA upregulation (18 h) and rapid VEGFR-2 phosphorylation (5 min), indicating direct transactivation of VEGFR-2 signaling. Real-time PCR; Matrigel tube formation with receptor antagonists; Western blot for VEGFR-2 phosphorylation International journal of molecular medicine Medium 20596610
2011 RAMP2 haploinsufficiency in female mice causes severe reproductive defects (fetal growth restriction, fetal demise, postnatal lethality), hyperprolactinemia, enlarged pituitary, accelerated mammary development, and skeletal abnormalities including decreased bone mineral density, demonstrating a physiological role for RAMP2 beyond AM/CLR signaling. RAMP2+/- mouse model; reproductive outcome analysis; serum prolactin measurement; pituitary and skeletal histomorphometry; bone mineral density measurement Molecular endocrinology (Baltimore, Md.) High 21566080
2011 AM-RAMP2 signaling is required for differentiation of liver sinusoidal endothelial-like cells from embryoid bodies; co-administration of AM and TGFβ receptor inhibitor SB431542 markedly enhanced LYVE-1/stabilin-2-positive endothelial cell differentiation. In RAMP2-null liver, LYVE-1 was downregulated in LSECs and sinusoidal structure was disrupted. Embryoid body differentiation system; AM co-administration with SB431542; LYVE-1/stabilin-2 immunostaining; LSEC marker expression; RAMP2 knockout liver histology Peptides Medium 21782867
2013 The endothelial AM-RAMP2 system regulates vascular integrity by controlling the Rac1-GTP/RhoA-GTP ratio and cortical actin formation; loss of endothelial RAMP2 causes actin disarrangement and EC detachment, leading to vascular leakage, spontaneous vasculitis, organ fibrosis, and accelerated vascular senescence. Endothelial-specific RAMP2 KO mice (E-RAMP2-/-) and drug-inducible DI-E-RAMP2-/- mice; vascular permeability assays; Rac1-GTP/RhoA-GTP measurement; actin cytoskeleton imaging; organ histopathology Circulation High 23355623
2013 The AM-RAMP2 system is required for retinal angiogenesis: heterozygous RAMP2+/- mice show reduced neovascular tufts, VEGF and eNOS mRNA in oxygen-induced retinopathy; DI-E-RAMP2-/- mice show abnormal developmental retinal vascular patterns; AM enhances proliferation and migration of retinal endothelial cells in vitro. OIR model in RAMP2+/- mice; drug-inducible EC-specific RAMP2 KO; retinal endothelial cell proliferation/migration assays; VEGF/eNOS mRNA quantification; intravitreal anti-ADM antibody injection The American journal of pathology High 23562442
2014 RAMP2 and RAMP3 have functionally distinct roles in the vascular system: RAMP2-/- mice die in utero due to blood vessel abnormalities (essential for vascular development), while RAMP3-/- mice are born normally but show delayed lymphatic drainage and impaired lymphatic endothelial cell migration. RAMP2-/- and RAMP3-/- mouse generation; ICG lymphangiography; tail lymphedema model; scratch-wound migration assay of lymphatic endothelial cells; histology Journal of molecular and cellular cardiology High 25264174
2014 The AM-RAMP2 system suppresses ER stress-induced tubule cell death in the kidney: AM suppresses PERK activation and CHOP-induced apoptosis downstream of ER stress in human RPTECs; in RAMP2+/- mice, tunicamycin-induced tubular damage is enhanced and the rescue effect of exogenous AM is lost. RAMP2+/- mice; STZ and tunicamycin-induced renal injury models; human RPTEC cell culture; Western blot for PERK/CHOP activation; histological analysis of tubular damage; AM rescue experiments PloS one High 24505304
2015 RAMP2 modulates glucagon receptor (GCGR) pharmacology: RAMP2 association alters ligand selectivity and G protein preference of GCGR, and abolishes novel cross-reactivity of GLP-1 receptor agonists at the glucagon receptor. Yeast reporter assays; mammalian cell functional assays; multiple ligand pharmacology; G protein coupling analysis The Journal of biological chemistry Medium 26198634
2016 Endothelial AM-RAMP2 system suppresses tumor metastasis: DI-E-RAMP2-/- mice show enhanced vascular permeability, endothelial-mesenchymal transition-like changes, and formation of pre-metastatic niches with S100A8/9 and SAA3 chemotactic factor expression; RAMP2 overexpression suppresses tumor cell adhesion to endothelial cells and metastasis. DI-E-RAMP2-/- mice; spontaneous and transplant tumor metastasis models; vascular permeability assays; immunostaining for S100A8/9, SAA3, inflammatory markers; RAMP2 overexpression in endothelial cells Cardiovascular research High 27307317
2017 RAMP2 co-expression with GCGR reduces GCGR cell surface expression, causes GCGR cellular redistribution (RAMP2 colocalizes with GCGR intracellularly), alters signaling through Gαs and Gαq pathways, and affects β-arrestin recruitment. Co-expression in cells; confocal microscopy co-localization; cell surface ELISA; competition binding; functional assays for Gαs, Gαq, β-arrestin; siRNA knockdown Endocrinology Medium 28586439
2017 The endothelial AM-RAMP2 system exerts vasoprotective effects after vascular injury: RAMP2+/- mice and DI-E-RAMP2-/- mice show enhanced neointima formation, greater macrophage infiltration and oxidative stress, and reduced re-endothelialization; the AM-RAMP2 system also augments proliferation and migration of endothelial progenitor cells. Wire-induced vascular injury model in RAMP2+/- and DI-E-RAMP2-/- mice; bone marrow transplantation; histology; endothelial progenitor cell proliferation/migration assays Endocrinology High 28324104
2019 RAMP2 pathogenic variants (Glu39Asp, Glu54Lys, Phe103Ser, Asn113Lysfs*10, Glu143Lys, Ser171Arg) cause aggregation of mutant RAMP2 in transfected cells and disrupt the AM-RAMP2/CRLR-cAMP signaling pathway; ablation of one Ramp2 allele leads to cAMP reduction and retinal ganglion cell death in mice. Exome sequencing; Sanger sequencing validation; heterologous expression of mutant RAMP2 proteins; RAMP2 protein aggregation imaging; cAMP measurement; heterozygous Ramp2 KO mouse retinal histology Genetics in medicine High 31000793
2019 CRFR1α and CRFR1β (but not CRFR2β) physically interact with RAMP2 to enhance its cell surface expression; ligand-stimulated CRFR1 causes loss of cell-surface RAMP2; CRFR2β does not interact with RAMP2, potentially due to a histidine (vs. glutamate in CRFR1) in the predicted contact interface. Co-expression in four cell lines; cell-surface ELISA for FLAG-RAMP2; RT-PCR for endogenous RAMPs; molecular modelling; CRF pre-treatment experiments Biochimica et biophysica acta. Biomembranes Medium 30826286
2021 RAMP2 alters GCGR subcellular trafficking: RAMP2 induces GCGR internalisation both basally and upon agonist stimulation, retains GCGR intracellularly, biases GCGR away from β-arrestin-2 recruitment toward increased Gαs activation at endosomes, and increases short-term cAMP production while enhancing long-term lysosomal targeting for degradation. Confocal microscopy; trafficking assays; radioligand binding; WASH complex KO MEFs; monensin; NanoBiT complementation; cAMP assays; hepatic AAV RAMP2 overexpression in mice Molecular metabolism High 34271220
2021 Cardiomyocyte-specific RAMP2 deletion (C-RAMP2-/-) after transverse aortic constriction causes cardiac hypertrophy, decreased ejection fraction, increased fibrosis, and reduced mitochondrial membrane potential and respiratory capacity, indicating the AM-RAMP2 system is required for early cardiac adaptation to stress via regulation of cardiac mitochondria. Cardiomyocyte-specific RAMP2 KO mice; TAC model; echocardiography; pressure-volume analysis; mitochondrial membrane potential and respiratory capacity assays; isoproterenol stimulation of isolated cardiomyocytes Endocrinology High 33545715
2022 RAMP2 acts as a specific allosteric modulator of PTH1R, shifting it to a preactivated state that permits faster ligand-dependent activation; RAMP2 modulates PTH1R downstream signaling in an agonist-dependent manner—most notably increasing PTH-mediated Gi3 signaling sensitivity—and increases β-arrestin2 recruitment triggered by both PTH and PTHrP. Optical biosensors measuring PTH1R activation and downstream signaling; RAMP2 co-expression; homology modelling for structural basis Proceedings of the National Academy of Sciences of the United States of America High 35914163
2023 RAMP2 acts as a negative allosteric modulator of the glucagon receptor (GCGR): cryo-EM structure of GCGR-Gs complex in the presence of RAMP2 shows the GCGR ECD is largely disordered; HDX-MS demonstrates RAMP2 enhances local flexibility in the ECD and the 6th transmembrane helix; smFRET shows ECD disorder inhibits active and intermediate states of the intracellular surface, broadly inhibiting downstream signaling. Cryo-EM structure determination (2.9 Å); HDX-MS; smFRET; downstream signaling assays Cell High 37001505
2023 Upregulation of Ramp2 in hepatocytes promotes proliferation of liver sinusoidal endothelial cells and hepatic revascularization after hepatectomy, acting via a shift from PEDF to VEGFA expression; overexpression of the competing factor Gata3 suppresses this pathway. AAV-mediated gene manipulation in Alb-Cre-CRISPR/Cas9 mice; partial hepatectomy and ALPPS models; endothelial precursor transfusion; patient-derived hepatic organoids; PEDF/VEGFA measurement Journal of hepatology Medium 37918568
2023 Endothelial RAMP2 contributes to ARDS pathogenesis by regulating vascular endothelial barrier function via Epac1; DI-E-RAMP2-/- mice after LPS challenge show reduced Epac1 expression, increased apoptosis, and reduced survival, while RAMP3 compensatorily upregulates; RAMP2 contributes primarily to circulation-regulating effects of AM. DI-E-RAMP2-/- and RAMP3-/- mice; intratracheal LPS model; lung pathology; survival analysis; transcriptomic analysis; Epac1, iNOS, TNF-α, NLRP3 expression Peptides Medium 38012983
2025 AM-RAMP2 signaling enhances pulmonary endothelial barrier integrity, anti-inflammatory phenotype (decreased ICAM1, increased IkBa), and anti-coagulation markers (increased THBD, decreased F3) under shear stress; blockade of RAMP2 completely attenuates these effects of ADM on lung endothelial cells. ECIS and XperT barrier integrity assays; RAMP2 blocking; RT-PCR and protein expression for homeostatic and inflammatory markers under shear stress in human pulmonary endothelial cells Cells Medium 41597226
2025 AM/RAMP2 signaling enhances endothelial cell homeostasis synergically with shear stress, maintaining CDH5, NOS3, TEK, S1PR1 expression and improving anti-coagulation; RAMP2 blockade abolishes ADM's effects on lung endothelial cells. ECIS barrier assay; shear stress perfusion system; pharmacological RAMP2 blockade; gene expression analysis bioRxivpreprint Low bio_10.1101_2025.09.21.677608
2025 In experimental autoimmune uveitis, AM exerts anti-inflammatory effects through RAMP2 by increasing regulatory T cells and M2 macrophages; RAMP2KO (but not RAMP3KO) mice show significantly worsened retinal inflammatory cell infiltration and clinical scores, demonstrating RAMP2-specific mediation of AM's immunomodulatory function. RAMP2KO and RAMP3KO mice; EAU mouse model; flow cytometry for Tregs and M2 macrophages; retinal T cell and macrophage quantification; cytokine RT-PCR; AM administration rescue Investigative ophthalmology & visual science Medium 40465267

Source papers

Stage 0 corpus · 44 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 The GPCR modulator protein RAMP2 is essential for angiogenesis and vascular integrity. The Journal of clinical investigation 162 18097473
2003 CL/RAMP2 and CL/RAMP3 produce pharmacologically distinct adrenomedullin receptors: a comparison of effects of adrenomedullin22-52, CGRP8-37 and BIBN4096BS. British journal of pharmacology 117 12970090
1999 The RAMP2/CRLR complex is a functional adrenomedullin receptor in human endothelial and vascular smooth muscle cells. FEBS letters 114 10217420
2004 Effects of adrenomedullin on endothelial cells in the multistep process of angiogenesis: involvement of CRLR/RAMP2 and CRLR/RAMP3 receptors. International journal of cancer 111 14712479
2013 Vascular endothelial adrenomedullin-RAMP2 system is essential for vascular integrity and organ homeostasis. Circulation 81 23355623
2007 Frequent inactivation of RAMP2, EFEMP1 and Dutt1 in lung cancer by promoter hypermethylation. Clinical cancer research : an official journal of the American Association for Cancer Research 74 17671114
2015 Modulation of Glucagon Receptor Pharmacology by Receptor Activity-modifying Protein-2 (RAMP2). The Journal of biological chemistry 61 26198634
2020 Exosomal lncRNA RAMP2-AS1 Derived from Chondrosarcoma Cells Promotes Angiogenesis Through miR-2355-5p/VEGFR2 Axis. OncoTargets and therapy 57 32368088
2001 The seven amino acids of human RAMP2 (86) and RAMP3 (59) are critical for agonist binding to human adrenomedullin receptors. The Journal of biological chemistry 53 11591721
2016 The endothelial adrenomedullin-RAMP2 system regulates vascular integrity and suppresses tumour metastasis. Cardiovascular research 51 27307317
2023 Negative allosteric modulation of the glucagon receptor by RAMP2. Cell 44 37001505
2003 Changes in the expression of calcitonin receptor-like receptor, receptor activity-modifying protein (RAMP) 1, RAMP2, and RAMP3 in rat uterus during pregnancy, labor, and by steroid hormone treatments. Biology of reproduction 41 12801991
2015 Adrenomedullin-RAMP2 System in Vascular Endothelial Cells. Journal of atherosclerosis and thrombosis 35 26040754
2014 Functional differentiation of RAMP2 and RAMP3 in their regulation of the vascular system. Journal of molecular and cellular cardiology 34 25264174
2011 Research resource: Haploinsufficiency of receptor activity-modifying protein-2 (RAMP2) causes reduced fertility, hyperprolactinemia, skeletal abnormalities, and endocrine dysfunction in mice. Molecular endocrinology (Baltimore, Md.) 32 21566080
2017 RAMP2 Influences Glucagon Receptor Pharmacology via Trafficking and Signaling. Endocrinology 29 28586439
2001 Adrenomedullin signalling in cardiomyocytes is dependent upon CRLR and RAMP2 expression. Peptides 28 11754972
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
2021 Receptor Activity-Modifying Protein 2 (RAMP2) alters glucagon receptor trafficking in hepatocytes with functional effects on receptor signalling. Molecular metabolism 22 34271220
2003 Changes of adrenomedullin and receptor activity modifying protein 2 (RAMP2) in myocardium and aorta in rats with isoproterenol-induced myocardial ischemia. Peptides 22 12732346
2022 Functional modulation of PTH1R activation and signaling by RAMP2. Proceedings of the National Academy of Sciences of the United States of America 21 35914163
2011 Induction of LYVE-1/stabilin-2-positive liver sinusoidal endothelial-like cells from embryoid bodies by modulation of adrenomedullin-RAMP2 signaling. Peptides 21 21782867
2014 Adrenomedullin-RAMP2 system suppresses ER stress-induced tubule cell death and is involved in kidney protection. PloS one 20 24505304
2022 RAMP2-AS1 inhibits CXCL11 expression to suppress malignant phenotype of breast cancer by recruiting DNMT1 and DNMT3B. Experimental cell research 19 35390315
2019 Mutant RAMP2 causes primary open-angle glaucoma via the CRLR-cAMP axis. Genetics in medicine : official journal of the American College of Medical Genetics 19 31000793
2004 RAMP2 and RAMP3 mRNA levels are increased in failing rat cardiomyocytes and associated with increased responsiveness to adrenomedullin. Journal of molecular and cellular cardiology 19 15623431
2013 Adrenomedullin-RAMP2 system is crucially involved in retinal angiogenesis. The American journal of pathology 18 23562442
2023 Balance of Gata3 and Ramp2 in hepatocytes regulates hepatic vascular reconstitution in postoperative liver regeneration. Journal of hepatology 17 37918568
2017 Vasoprotective Activities of the Adrenomedullin-RAMP2 System in Endothelial Cells. Endocrinology 17 28324104
2006 Gene silencing of human RAMP2 mediated by short-interfering RNA. International journal of molecular medicine 16 16964401
2019 Interactions between RAMP2 and CRF receptors: The effect of receptor subtypes, splice variants and cell context. Biochimica et biophysica acta. Biomembranes 15 30826286
2021 RAMP2-AS1 Regulates Endothelial Homeostasis and Aging. Frontiers in cell and developmental biology 14 33644072
2014 Pathophysiological roles of adrenomedullin-RAMP2 system in acute and chronic cerebral ischemia. Peptides 14 25252154
2017 Genetic Variants of RAMP2 and CLR are Associated with Stroke. Journal of atherosclerosis and thrombosis 13 28904253
2003 Changes in amount of ADM mRNA and RAMP2 mRNA in calcified vascular smooth muscle cells. Peptides 13 12668214
2024 Identification of a hypoxia-suppressed lncRNA RAMP2-AS1 in breast cancer. Non-coding RNA research 10 38590436
2021 Adrenomedullin-RAMP2 and -RAMP3 Systems Regulate Cardiac Homeostasis during Cardiovascular Stress. Endocrinology 9 33545715
2001 Phenotypic changes of adrenomedullin receptor components, RAMP2, and CRLR mRNA expression in cultured rat vascular smooth muscle cells. Biochemical and biophysical research communications 9 11676473
2023 Receptor activity-modifying proteins of adrenomedullin (RAMP2/3): Roles in the pathogenesis of ARDS. Peptides 6 38012983
2025 Adrenomedullin-RAMP2 System Modulates Inflammation and Tissue Repair in Experimental Autoimmune Uveitis Via T-Cell and M2 Macrophage Regulation. Investigative ophthalmology & visual science 3 40465267
2023 RAMP2-AS1 stabilized RAPM2 mRNA through TIA1 to inhibit the progression of non-small cell lung cancer. Cellular and molecular biology (Noisy-le-Grand, France) 2 38279501
2024 Serum lncRNA RAMP2-AS1 Served as a Biomarker of Deep Vein Thrombosis Occurrence and Development in Elderly. Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion 1 39469176
2026 Adrenomedullin-RAMP2 Enhances Lung Endothelial Cell Homeostasis Under Shear Stress. Cells 0 41597226
2015 [Adrenomedullin-Receptor Activity-modifying Protein 2 (RAMP2) System in Retinal Angiogenesis]. Nippon Ganka Gakkai zasshi 0 26685480

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