Affinage

RAMP3

Receptor activity-modifying protein 3 · UniProt O60896

Round 2 corrected
Length
148 aa
Mass
16.5 kDa
Annotated
2026-04-28
54 papers in source corpus 27 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAMP3 is a single-transmembrane accessory protein that heterodimerizes with multiple GPCRs to regulate their trafficking, pharmacology, and signaling. It was originally identified as a chaperone that escorts the calcitonin receptor-like receptor (CLR) to the cell surface, where CLR/RAMP3 forms the AM2 adrenomedullin receptor, with residues 59–65 and Glu74 in the RAMP3 extracellular domain determining high-affinity AM binding (PMID:9620797, PMID:11591721, PMID:18593822). A unique C-terminal PDZ motif distinguishes RAMP3 from RAMP1/RAMP2 by recruiting NSF to redirect internalized receptor complexes from lysosomal degradation to Rab4-positive recycling endosomes, a mechanism operative for both CLR and the atypical chemokine receptors ACKR3 and ACKR2 (PMID:15613468, PMID:31712427, PMID:39437486). In vivo, RAMP3 is required for lymphatic vessel function, ACKR3-dependent retinal angiogenesis, amylin-mediated satiation signaling, GPR30-dependent cardioprotection, and glucose homeostasis (PMID:25264174, PMID:31712427, PMID:31881259, PMID:23674134).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1998 High

    Identification of RAMP3 as part of a new family of single-TM accessory proteins required for CRLR plasma membrane delivery and ligand-specificity switching (CGRP vs. AM receptor) resolved the longstanding paradox of how a single receptor generated two pharmacologically distinct binding phenotypes.

    Evidence Co-expression in cell lines with radioligand binding and cAMP assays

    PMID:9620797

    Open questions at the time
    • Stoichiometry and direct physical interaction not yet demonstrated
    • Mechanism of selectivity switch unknown
  2. 1999 High

    Demonstration that RAMP3 also partners with the calcitonin receptor to generate a distinct amylin receptor (AMY3R) established that RAMPs are not CRLR-specific accessories but general GPCR modulators, and showed RAMP3 requires a receptor partner for surface expression.

    Evidence Co-transfection in COS-7 cells with radioligand binding, cAMP assays, and confocal microscopy

    PMID:10385705

    Open questions at the time
    • Full repertoire of RAMP3-interacting GPCRs unknown
    • Structural basis of AMY3R vs. AMY1R selectivity unresolved
  3. 2001 High

    Cross-linking and mutagenesis studies established that RAMP3 directly contacts the ligand-binding pocket and that residues 59–65 in its extracellular domain are critical for AM binding, shifting the mechanistic model from glycosylation-dependent to direct protein–protein interaction-dependent pharmacology.

    Evidence Cross-linking with 125I-AM, RAMP chimera/deletion mutagenesis with radioligand binding and cAMP assays in HEK293 cells

    PMID:11387328 PMID:11591721

    Open questions at the time
    • High-resolution structure of the RAMP3–CLR interface not available
    • Contribution of individual residues within 59–65 not dissected
  4. 2003 High

    Post-translational requirements for RAMP3 function were defined: N-glycosylation and disulfide bonds formed by all six conserved cysteines are essential for functional AM receptor expression, and pharmacological profiling established that AM2R (CLR/RAMP3) has distinct antagonist sensitivity from AM1R (CLR/RAMP2).

    Evidence Mutagenesis in Xenopus oocytes and pharmacological characterization in COS-7 cells with cAMP assays

    PMID:12939163 PMID:12970090

    Open questions at the time
    • Structure of RAMP3 ECD not solved
    • Species-dependent pharmacological differences not fully explained mechanistically
  5. 2004 High

    Discovery that the C-terminal PDZ motif unique to RAMP3 recruits NSF to reroute internalized CLR/RAMP3 from degradation to recycling answered why AM2R resensitizes more efficiently than AM1R and introduced a trafficking-based mechanism for differential RAMP function.

    Evidence Mutagenesis, RNAi, and pharmacological NSF inhibition in HEK293 and rat mesangial cells with cAMP, binding, and immunofluorescence readouts

    PMID:15613468

    Open questions at the time
    • Identity of PDZ domain-containing scaffold linking RAMP3 to NSF not determined
    • Whether recycling mechanism applies to non-CLR partners unknown at this point
  6. 2008 High

    Systematic mutagenesis pinpointed Glu74 as the single residue most critical for differential AM potency between AM2R and CGRP receptor, providing the first residue-level explanation for RAMP-dependent pharmacological switching.

    Evidence Site-directed mutagenesis of eight conserved positions in RAMP1/RAMP3 with cAMP and surface expression assays

    PMID:18593822 PMID:21402116

    Open questions at the time
    • Structural context of Glu74 within the peptide-binding interface not visualized
    • Role in intermedin/AM2 binding not fully assessed
  7. 2013 High

    RAMP3 was shown to physically interact with GPR30 (GPER1), a non-class-B GPCR, expanding the interactome well beyond CLR/CTR; in vivo, RAMP3 deletion abolished GPR30-agonist-mediated cardioprotection in a sex-dependent manner.

    Evidence BRET, co-IP, confocal in HEK293; RAMP3 KO mice with TAC and G-1 treatment; cardiac histopathology

    PMID:23674134

    Open questions at the time
    • Mechanism by which RAMP3 modulates GPR30 signaling (trafficking vs. coupling) not dissected
    • Sex-dependence mechanism unclear
  8. 2014 High

    RAMP3 knockout mice revealed a non-redundant role for RAMP3 in lymphatic vessel function — lymphatic drainage, chyle transport, and lymphatic endothelial cell migration were all impaired — distinguishing RAMP3 from RAMP2 whose loss causes embryonic-lethal vascular defects.

    Evidence Global RAMP3 KO mice; ICG lymphangiography; tail lymphedema model; isolated lymphatic EC migration assay

    PMID:25264174

    Open questions at the time
    • Which RAMP3 receptor partner mediates lymphatic effects not identified
    • Whether PDZ-dependent recycling is involved in lymphatic function untested
  9. 2019 High

    Three independent 2019 studies collectively broadened RAMP3 biology: (1) RAMP3 interaction with ACKR3 enables Rab4-dependent receptor recycling and AM scavenging required for retinal angiogenesis; (2) RAMP3 in cancer-associated fibroblasts regulates podoplanin via Src/Cas signaling to promote metastasis; (3) RAMP3 KO mice are glucose intolerant and lose amylin-mediated anorexia, establishing RAMP3 in metabolic homeostasis.

    Evidence BRET screens, Rab4 trafficking assays, retinal angiogenesis in KO mice; syngeneic tumor metastasis models with Src/Cas pathway analysis; metabolic phenotyping of global RAMP1/RAMP3 KO mice with amylin/sCT injection

    PMID:31712427 PMID:31754214 PMID:31881259

    Open questions at the time
    • Whether RAMP3 PDZ motif mediates ACKR3 recycling specifically through NSF not shown
    • CAF findings from single cancer model
    • Brain region-specific RAMP3 function in satiation not mapped
  10. 2020 High

    Cryo-EM structures of AM2R (CLR/RAMP3) at 2.3–2.4 Å resolution revealed how RAMP3 ECD orientation and the linker region between TM and ECD control receptor phenotype, providing the first atomic-level explanation for RAMP-dependent pharmacology.

    Evidence Cryo-EM of AM2R–AM–Gs and AM2R–intermedin–Gs; chimeric RAMP linker swaps

    PMID:32296767

    Open questions at the time
    • No structure of RAMP3 in complex with CTR (AMY3R) at this time
    • Intracellular PDZ domain region not resolved
  11. 2022 High

    Cryo-EM of AMY3R (CTR/RAMP3) showed that RAMP3 constrains amylin binding through a midpeptide bypass motif and that calcitonin-based versus amylin-based activation proceeds through structurally distinct mechanisms, explaining peptide-dependent signaling differences.

    Evidence Cryo-EM structures of AMY3R–amylin and related CTR/RAMP complexes with multiple peptides

    PMID:35324283

    Open questions at the time
    • Structures are Gs-coupled only; Gq or Gi-coupled states unknown
    • RAMP3 C-terminal PDZ motif still not resolved structurally
  12. 2024 Medium

    RAMP3 was shown to promote ACKR2 membrane expression via Rab4 vesicles and enable CCL2 scavenging in hepatocellular carcinoma cells, extending the RAMP3-dependent recycling mechanism to a second atypical chemokine receptor and linking it to tumor immune microenvironment regulation.

    Evidence Co-IP, overexpression/knockdown in HCC cell lines, syngeneic tumors, CCL2 ELISA, flow cytometry for myeloid infiltration

    PMID:39437486

    Open questions at the time
    • Whether RAMP3 PDZ motif or another domain mediates ACKR2 interaction not determined
    • Single tumor model
    • Independent replication needed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of the RAMP3 C-terminal PDZ motif–NSF interaction, the full inventory of RAMP3-interacting GPCRs, and how RAMP3 biases G-protein coupling selectivity (e.g., at GLP-1R) at a structural level.
  • No crystal or cryo-EM structure of the RAMP3 PDZ motif with NSF or other scaffold
  • Comprehensive unbiased interactome screen for RAMP3 across all GPCRs not performed
  • Mechanism of G-protein coupling bias by RAMP3 structurally undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0098772 molecular function regulator activity 5 GO:0048018 receptor ligand activity 2
Localization
GO:0005886 plasma membrane 5 GO:0005768 endosome 3 GO:0031410 cytoplasmic vesicle 3
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-392499 Metabolism of proteins 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-1266738 Developmental Biology 2
Partners
ACKR2ACKR3CALCRCALCRLGPER1NSFPTH2R
Complex memberships
ACKR3/RAMP3AM2R (CLR/RAMP3)AMY3R (CTR/RAMP3)GPR30/RAMP3

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 RAMP3, together with RAMP1 and RAMP2, forms a family of single-transmembrane-domain proteins required to transport the calcitonin receptor-like receptor (CRLR) to the plasma membrane; RAMP2- or RAMP3-transported CRLR functions as an adrenomedullin receptor, whereas RAMP1-transported CRLR functions as a CGRP receptor. Transfection/co-expression in cell lines with radioligand binding and functional cAMP assays Nature High 9620797
1999 RAMP3 co-expressed with the calcitonin receptor (CTR) generates a distinct amylin receptor phenotype (AMY3R) with reduced efficacy for human CGRPα compared to the RAMP1/CTR (AMY1R) combination; RAMP3 is located intracellularly when expressed alone but traffics to the cell surface upon co-expression with CTR. Co-transfection in COS-7 cells, 125I-amylin radioligand binding competition, cAMP functional assays, confocal microscopy with c-myc-tagged RAMP1, and cross-linking experiments Molecular pharmacology High 10385705
2000 CRLR is endocytosed together with RAMP3 (and RAMP1/2) via clathrin-coated vesicles following agonist stimulation; internalized CRLR/RAMP complexes are largely targeted to a degradative (lysosomal) pathway with inefficient recycling, and CRLR cannot reach the plasma membrane without RAMPs. Stable expression of CRLR-GFP chimera ± RAMPs in HEK293 cells; agonist-stimulated internalization tracked by fluorescence microscopy; hypertonic sucrose inhibition of clathrin-dependent endocytosis; co-localization with rhodamine-transferrin and lysosomal markers The Journal of biological chemistry High 10882736
2001 Direct protein–protein interaction between RAMP3 (or RAMP2) and CRLR, not differential glycosylation, determines ligand-binding selectivity: cross-linking experiments showed that 125I-AM is incorporated into RAMP2 and RAMP3 within the CRLR-RAMP heterodimer, placing the RAMPs close to the peptide-binding pocket; fully glycosylated CRLR, not the core-glycosylated form produced by RAMP2/3 co-expression, represents the functional AM-binding receptor. Co-expression in HEK293 cells, cross-linking with bis-succinimidyl suberate, radioligand binding (125I-AM, 125I-CGRP), glycosylation analysis The Journal of biological chemistry High 11387328
2001 Seven specific amino acids in the extracellular N-terminal domain of RAMP3 (residues 59–65) are critical for high-affinity AM binding and AM-evoked cAMP production at the CRLR/RAMP3 adrenomedullin receptor; deletion of this segment significantly attenuates 125I-AM binding despite preserved cell-surface expression of the receptor heterodimer. RAMP chimeras and deletion mutants co-expressed with CRLR in HEK293 cells; 125I-AM radioligand binding; AM-evoked cAMP production assay; cell-surface expression confirmed by ELISA The Journal of biological chemistry High 11591721
2002 RAMP3 interacts with the PTH2 receptor (in addition to CRLR and CTR), extending the known repertoire of RAMP3 receptor partners to at least one additional class II GPCR; RAMP-receptor complexes beyond CL/CTR can modulate downstream signaling. Immunofluorescence confocal microscopy co-localization; radioligand binding in COS-7 cells; phosphoinositide hydrolysis assay The Journal of biological chemistry Medium 12446722
2003 N-glycosylation of RAMP3 (at two to four of its four consensus sites) and disulfide bonds formed by all six conserved cysteine residues in its extracellular domain are each essential for functional expression of the CRLR/RAMP3 adrenomedullin receptor: elimination of all N-glycans reduces 125I-AM binding and increases EC50, while mutation of all cysteines to serine completely abolishes AM binding. Xenopus oocyte expression system; site-directed mutagenesis of N-glycosylation sites and cysteines; 125I-AM radioligand binding; EC50 determination for AM-evoked responses Biochemistry High 12939163
2003 CL/RAMP2 and CL/RAMP3 receptors are pharmacologically distinct: AM22-52 selectively antagonizes CL/RAMP2 over CL/RAMP3 in human receptor combinations, whereas CGRP8-37 is an effective antagonist at CL/RAMP3 but shows species-dependent effects at CL/RAMP2; the agonist potency order at CL/RAMP3 is AM ≈ βCGRP > αCGRP. Transient transfection in COS-7 cells and endogenous receptor expression in Rat 2 and L6 cells; cAMP functional assays with peptide antagonists; apparent pA2 determination British journal of pharmacology High 12970090
2004 The C-terminal PDZ type I motif unique to RAMP3 (absent from RAMP1 and RAMP2) mediates interaction with N-ethylmaleimide-sensitive factor (NSF), redirecting the CRLR/RAMP3 (AM2R) complex from a degradative pathway to a recycling pathway after agonist-stimulated internalization; deletion or point mutation of the PDZ motif abolishes this NSF interaction and recycling. Adenylate cyclase assays, radioligand binding, immunofluorescence microscopy in HEK293 cells; mutational analysis (deletion and point mutations of PDZ motif); RNA interference of RAMP3 in rat mesangial cells; pharmacological inhibition of NSF The Journal of biological chemistry High 15613468
2005 Parathyroid hormone (PTH) induces RAMP3 mRNA expression in primary mouse osteoblasts as a primary response gene (cycloheximide-insensitive) primarily through the cAMP–PKA signaling pathway; PKA inhibition with H89 blocks PTH- and forskolin-induced RAMP3 upregulation, whereas PKC activation with PMA also increases RAMP3 but calcium signaling (ionomycin) does not. Primary mouse osteoblast cultures; representational difference analysis; RT-PCR for RAMP3 mRNA; pharmacological dissection using cycloheximide, forskolin, H89 (PKA inhibitor), PMA (PKC activator/depletor), ionomycin, and PTH(3-34) Calcified tissue international Medium 16075364
2008 Residue 74 in RAMP3 (Glu74) is a key determinant of AM pharmacology at the CL/RAMP3 (AM2) receptor; substitution of RAMP3 residues into RAMP1 and vice versa at position 74 converts AM potency profiles, with RAMP1 Phe93 additionally contributing to αCGRP potency at the CGRP receptor. Site-directed mutagenesis of RAMP1 and RAMP3 at eight conserved positions; co-transfection with CL or CTR in COS-7 cells; agonist-stimulated cAMP production; cell-surface expression by ELISA Molecular pharmacology High 18593822
2009 RAMP3 is an early Wnt target gene: in C57MG cells stimulated with Wnt-3a, RAMP3 mRNA is induced within 1–6 hours, classifying it as an early (not immediate or late) transcriptional target of canonical Wnt/β-catenin signaling. Wnt-3a stimulation of C57MG cells; time-course RT-PCR for RAMP3 and other Wnt target genes; comparison of induction kinetics Cell biology international Medium 19353769
2010 Structure–function analysis of RAMP1–RAMP3 chimeras reveals that extracellular helix 1 and residues 62–69 of helix 2 are required for CRLR trafficking (CLR association), while residues 86–89 at the helix 2/3 junction influence peptide (αCGRP and AM) binding potency without affecting trafficking; RAMP3 chimera data suggest the helix 2/3 loop is less exposed than in RAMP1 and plays a role in peptide binding. RAMP1/RAMP3 chimera co-expression with CLR or CTR in COS-7 cells; CLR trafficking assay; agonist-stimulated cAMP production; homology modeling Biochemistry Medium 20017504
2011 Glu74 in RAMP3 specifically contributes to AM potency at the AM2 (CL/RAMP3) receptor through geometry and charge: Phe substitution reduces AM potency while Tyr does not, and most other substitutions have small effects; the equivalent residue Trp74 in RAMP1 has distinct behavior (Tyr enhances AM potency), confirming position 74 as a key differential determinant between AM2 and CGRP receptors. Site-directed mutagenesis of Glu74 in RAMP3 and Trp74 in RAMP1 with multiple amino acid substitutions; co-expression with CLR in COS-7 cells; cAMP assay for AM, AM2/intermedin, and CGRP; cell-surface expression by ELISA Peptides High 21402116
2013 RAMP3 physically interacts with GPR30 (G-protein-coupled estrogen receptor 1/GPER1): BRET titration, co-immunoprecipitation, and confocal microscopy demonstrate direct interaction; GPR30 presence increases RAMP3 plasma membrane expression in HEK293 cells; in vivo, RAMP3 knockout disrupts GPR30 subcellular localization in cardiac cells and abolishes GPR30-agonist (G-1)-mediated reduction of cardiac hypertrophy and perivascular fibrosis in a sex-dependent manner. BRET titration assays, co-immunoprecipitation, confocal microscopy in HEK293 cells; in vivo RAMP3 knockout mice on heart disease-prone background treated with G-1; cardiac histopathology Journal of molecular endocrinology High 23674134
2014 RAMP3 knockout mice are viable and display normal postnatal blood vessel angiogenesis, but exhibit delayed lymphatic drainage (shown by ICG lymphangiography), delayed chyle transport by intestinal lymphatics, more severe interstitial edema in a tail lymphedema model, and a primary migration defect in isolated RAMP3−/− lymphatic endothelial cells that is not rescued by AM; RAMP2 knockout (but not RAMP3 knockout) is embryonically lethal due to vascular defects, establishing distinct functional roles for the two AM receptor subtypes. RAMP2−/− and RAMP3−/− mouse generation; ICG lymphangiography; tail lymphedema model with histology; in vitro scratch-wound migration assay of isolated lymphatic endothelial cells Journal of molecular and cellular cardiology High 25264174
2015 In rat mesenteric artery smooth muscle cells (VSMCs), RAMP3 (not RAMP2) associates with CALCRL to mediate ADM-induced cAMP production; RAMP3 knockdown inhibits ADM-induced cAMP generation and ADM–CALCRL association; proximity ligation assay directly demonstrates RAMP3–CALCRL co-localization enhanced by ADM. RAMP2/RAMP3 siRNA knockdown in VSMCs; cAMP production assay with peptide antagonists; proximity ligation assay for RAMP3–CALCRL association Biology of reproduction Medium 26423127
2019 RAMP3 interacts with atypical chemokine receptor 3 (ACKR3) and is required for rapid recycling of ACKR3 to the plasma membrane through Rab4-positive vesicles following AM or SDF-1/CXCL12 binding; RAMP3–ACKR3 interaction reduces AM ligand availability without changing G-protein coupling; genetic deletion of RAMP3 in mice abolishes directed retinal angiogenesis, phenocopying ACKR3 deletion. BRET-based and cell-surface expression screens for RAMP–chemokine receptor interactions; Rab4-positive vesicle trafficking assays; AM ligand scavenging assays; RAMP3 and ACKR3 global knockout mice; retinal angiogenesis imaging Proceedings of the National Academy of Sciences of the United States of America High 31712427
2019 RAMP3 deficiency in cancer-associated fibroblasts (CAFs) suppresses tumor metastasis by reducing podoplanin (PDPN)-positive CAF numbers at metastatic sites; RAMP3 regulates PDPN expression via Src/Cas/PDPN signaling in fibroblasts; RAMP3−/− CAFs show reduced migration, proliferation, and metastasis-promoting activity in co-cultures with tumor cells in vitro and in vivo. Splenic injection of PAN02 pancreatic cancer cells in RAMP3−/− and DI-E-RAMP2−/− mice for spontaneous liver metastasis model; podoplanin immunohistochemistry; Src/Cas pathway analysis; in vitro co-culture migration and proliferation assays Oncogene Medium 31754214
2019 RAMP3 knockout mice display glucose intolerance (on chow diet in males) and altered meal patterns (decreased intermeal interval); amylin and salmon calcitonin anorectic effects are mediated through distinct RAMP-containing receptor combinations: RAMP1/3 double KO mice are insensitive to both amylin and sCT, while RAMP3 KO mice respond to sCT but not amylin, indicating RAMP3 specifically mediates part of amylin's anorectic signaling. Global RAMP1, RAMP3, and RAMP1/3 double KO mice; glucose tolerance tests; intraperitoneal amylin and sCT injection with food intake measurement; meal pattern analysis; c-Fos immunohistochemistry in area postrema Neuroscience Medium 31881259
2019 RAMP3 alanine scanning of extracellular loops (ECL2 and ECL3) of the calcitonin receptor in the AMY3R context demonstrates that RAMP3 co-expression fundamentally alters the dynamic role of ECL2 and ECL3 in propagating cAMP and ERK signaling compared to CTR alone; the effects are highly peptide-dependent (sCT, hCT, pCT, rat amylin, hCGRP show distinct ECL mutation effects in the AMY3R context). Alanine scanning mutagenesis of CTR ECL2 and ECL3 co-expressed with RAMP3; cAMP accumulation assay; ERK phosphorylation (pERK) assay; cell-surface expression by ELISA ACS pharmacology & translational science Medium 32219220
2020 Cryo-EM structures of the AM2R (CL/RAMP3) in complex with AM or intermedin and Gs protein reveal that RAMP3 positions its extracellular domain (ECD) at a distinct primary orientation relative to the receptor core compared to RAMP2 in AM1R, and that the RAMP linker region connecting the TM helix and ECD controls receptor phenotype; distinct ECL3 positioning and ECD mobility are receptor-dependent features. Cryo-EM structure determination of AM2R–AM–Gs (2.4 Å) and AM2R–AM2–Gs (2.3 Å); chimeric RAMP linker exchange experiments; dynamic analysis of cryo-EM micrographs ACS pharmacology & translational science High 32296767
2021 Cardiomyocyte-specific RAMP3 knockout mice show normal baseline cardiac function but develop reduced systolic function and enhanced fibrosis after 4 weeks of transverse aortic constriction (TAC), with a characteristic reduction in cardiac lymphatic vessels, indicating that the AM–RAMP3 system is required for later adaptive cardiac responses to cardiovascular stress through regulation of lymphatic vessels. Cardiomyocyte-specific RAMP3 KO mice; TAC model; echocardiography; histological fibrosis quantification; cardiac lymphatic vessel immunostaining Endocrinology Medium 33545715
2022 Cryo-EM structures of AMY3R (CTR/RAMP3) with amylin and other calcitonin family peptides demonstrate that RAMP3 constrains the conformation of amylin-bound AMY3R through a midpeptide 'bypass motif', and that CT-based peptide activation of AMY3R is structurally distinct from amylin-based activation; these structural differences have direct implications for ligand selectivity. Cryo-EM structure determination of AMY3R–amylin, AMY1R–sCT, AMY2R–sCT/hCT, and CTR–amylin/sCT/hCT complexes; structural comparison and dynamics analysis Science High 35324283
2024 RAMP3 binds atypical chemokine receptor 2 (ACKR2) in HCC tumor cells and promotes ACKR2 membrane distribution through Rab4-positive vesicles, enabling ACKR2-mediated CCL2 scavenging/degradation; RAMP3 expression reduces intratumoral CCL2, inhibits STAT3 and AKT phosphorylation, and reduces CD11b+/Gr-1+ myeloid cell infiltration and neovascularization in syngeneic tumors through ACKR2. Co-IP and bioinformatic PPI analysis; overexpression and knockdown in Huh7, HepG2, and Hepa1-6 cells; syngeneic tumor implantation; CCL2 ELISA; STAT3/AKT phosphorylation Western blot; flow cytometry for myeloid infiltration; immunohistochemistry for neovascularization International immunopharmacology Medium 39437486
2025 RAMP3 interacts with the GLP-1 receptor (GLP-1R) and biases its signaling: RAMP3 co-expression reduces canonical Gαs/cAMP coupling while increasing Gαq and Gαi coupling, shifting the receptor toward Ca2+ mobilization; this altered signaling profile elevates glucose-stimulated insulin secretion in cells overexpressing RAMP3, and RAMP3 knockout mice show reduced sensitivity to GLP-1 in glucose and insulin tolerance tests. BRET assays for GLP-1R–RAMP3 interaction and G-protein coupling; Ca2+ mobilization assay; cAMP assay; glucose-stimulated insulin secretion assay; RAMP3 KO mouse glucose and insulin tolerance tests bioRxivpreprint Medium bio_10.1101_2025.01.24.634724
2024 AMY3R (CTR/RAMP3) has a stronger transmembrane domain interface than AMY1R or AMY2R, resulting in a more stable basal CTR–RAMP3 subunit association; calcitonin agonists (human and salmon CT) promote AMY3R dissociation, while rat amylin promotes AMY1/2R subunit association; these altered equilibria directly affect G-protein coupling and cAMP signaling output. Novel biochemical assay resolving AMYR heterodimers vs. free subunits; live-cell membrane subunit association assays; G-protein coupling assays; cAMP signaling assays bioRxivpreprint Medium bio_10.1101_2024.10.09.617487

Source papers

Stage 0 corpus · 54 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 1808 9620797
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
1999 Multiple amylin receptors arise from receptor activity-modifying protein interaction with the calcitonin receptor gene product. Molecular pharmacology 417 10385705
2003 Intermedin is a calcitonin/calcitonin gene-related peptide family peptide acting through the calcitonin receptor-like receptor/receptor activity-modifying protein receptor complexes. The Journal of biological chemistry 387 14615490
2002 Novel receptor partners and function of receptor activity-modifying proteins. The Journal of biological chemistry 243 12446722
2007 hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes. Genomics 222 17207965
2003 The DNA sequence of human chromosome 7. Nature 188 12853948
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
2003 Human chromosome 7: DNA sequence and biology. Science (New York, N.Y.) 154 12690205
2000 Visualization of the calcitonin receptor-like receptor and its receptor activity-modifying proteins during internalization and recycling. The Journal of biological chemistry 145 10882736
1999 RAMPs: accessory proteins for seven transmembrane domain receptors. Trends in pharmacological sciences 126 10354609
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
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 110 14712479
2002 Immunohistochemical localization of calcitonin receptor-like receptor and receptor activity-modifying proteins in the human cerebral vasculature. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 108 11973435
2001 Protein-protein interaction and not glycosylation determines the binding selectivity of heterodimers between the calcitonin receptor-like receptor and the receptor activity-modifying proteins. The Journal of biological chemistry 104 11387328
2004 Novel function for receptor activity-modifying proteins (RAMPs) in post-endocytic receptor trafficking. The Journal of biological chemistry 93 15613468
2008 Reviews in molecular biology and biotechnology: transmembrane signaling by G protein-coupled receptors. Molecular biotechnology 92 18240029
2012 Amyloid β (Aβ) peptide directly activates amylin-3 receptor subtype by triggering multiple intracellular signaling pathways. The Journal of biological chemistry 89 22500019
2020 Structure and Dynamics of Adrenomedullin Receptors AM1 and AM2 Reveal Key Mechanisms in the Control of Receptor Phenotype by Receptor Activity-Modifying Proteins. ACS pharmacology & translational science 79 32296767
2022 A structural basis for amylin receptor phenotype. Science (New York, N.Y.) 71 35324283
2008 Dissociation of heterotrimeric g proteins in cells. Science signaling 69 18577758
2012 Calcitonin and calcitonin receptor-like receptors: common themes with family B GPCRs? British journal of pharmacology 64 21649645
2008 Identification of N-terminal receptor activity-modifying protein residues important for calcitonin gene-related peptide, adrenomedullin, and amylin receptor function. Molecular pharmacology 63 18593822
2013 G-protein-coupled receptor 30 interacts with receptor activity-modifying protein 3 and confers sex-dependent cardioprotection. Journal of molecular endocrinology 61 23674134
2002 Increased myocardial expression of RAMP1 and RAMP3 in rats with chronic heart failure. Biochemical and biophysical research communications 55 12051717
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
2009 Chronological expression of Wnt target genes Ccnd1, Myc, Cdkn1a, Tfrc, Plf1 and Ramp3. Cell biology international 46 19353769
2019 RAMP3 determines rapid recycling of atypical chemokine receptor-3 for guided angiogenesis. Proceedings of the National Academy of Sciences of the United States of America 44 31712427
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
2019 RAMP1 and RAMP3 Differentially Control Amylin's Effects on Food Intake, Glucose and Energy Balance in Male and Female Mice. Neuroscience 34 31881259
2014 Functional differentiation of RAMP2 and RAMP3 in their regulation of the vascular system. Journal of molecular and cellular cardiology 34 25264174
2003 N-Glycosylation and conserved cysteine residues in RAMP3 play a critical role for the functional expression of CRLR/RAMP3 adrenomedullin receptor. Biochemistry 23 12939163
2019 Deficiency of the adrenomedullin-RAMP3 system suppresses metastasis through the modification of cancer-associated fibroblasts. Oncogene 22 31754214
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
2005 Parathyroid hormone induces receptor activity modifying protein-3 (RAMP3) expression primarily via 3',5'-cyclic adenosine monophosphate signaling in osteoblasts. Calcified tissue international 19 16075364
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
2019 Deconvoluting the Molecular Control of Binding and Signaling at the Amylin 3 Receptor: RAMP3 Alters Signal Propagation through Extracellular Loops of the Calcitonin Receptor. ACS pharmacology & translational science 10 32219220
2018 RAMP3 deficiency enhances postmenopausal obesity and metabolic disorders. Peptides 10 30385288
2021 Adrenomedullin-RAMP2 and -RAMP3 Systems Regulate Cardiac Homeostasis during Cardiovascular Stress. Endocrinology 9 33545715
2015 Involvement of Receptor Activity-Modifying Protein 3 (RAMP3) in the Vascular Actions of Adrenomedullin in Rat Mesenteric Artery Smooth Muscle Cells. Biology of reproduction 8 26423127
2010 Structure-function analysis of RAMP1-RAMP3 chimeras. Biochemistry 6 20017504
2005 Induction of BAALC and down regulation of RAMP3 in astrocytes treated with differentiation inducers. Cell biology international 6 16376586
2019 Analysis of RAMP3 gene polymorphism with body composition and bone density in young and elderly women. Gene: X 5 32550545
2021 Adrenomedullin 2 and 5 activate the calcitonin receptor-like receptor (clr) - Receptor activity-modifying protein 3 (ramp3) receptor complex in Xenopus tropicalis. General and comparative endocrinology 3 33711314
2019 Analysis of RAMP3 gene polymorphism with body composition and bone density in young and elderly women. Gene 2 34530989
2024 -RAMP3 promotes hepatocellular carcinoma tumor cell-mediated CCL2 degradation by supporting membrane distribution of ACKR2. International immunopharmacology 1 39437486