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Gene Review

RAMP1  -  receptor (G protein-coupled) activity...

Homo sapiens

Synonyms: CRLR activity-modifying protein 1, Calcitonin-receptor-like receptor activity-modifying protein 1, Receptor activity-modifying protein 1
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Disease relevance of RAMP1

  • In Xenopus oocytes with an endogenous calcitonin gene-related peptide (CGRP) receptor, a receptor activity modifying protein (RAMP1) enhancing CGRP stimulated chloride currents of the cystic fibrosis transmembrane regulator was recently cloned [McLatchie, L.M. et al. (1998) Nature 393, 333-339] [1].
  • We examined the expression of CRLR and RAMP1, 2, and 3 in several tissues from mice in a sepsis model induced by lipopolysaccharide (LPS) [2].
  • We examined the regulation of their expression in a rat model of renal injury and found that RAMP1, RAMP2 and CRLR expressions were markedly upregulated upon induction of fibrosis during obstructive nephropathy [3].
  • Decremental Ramp Atrial Extrastimuli Pacing Protocol for the Induction of Atrioventricular Nodal Re-entrant Tachycardia and Other Supraventricular Tachycardias [4].
  • Randomized comparison between Ramp and Burst+ atrial antitachycardia pacing therapies in patients suffering from sinus node disease and atrial fibrillation and implanted with a DDDRP device [5].

High impact information on RAMP1

  • The calcitonin-like receptor (CL receptor) requires a single transmembrane domain protein, termed receptor activity modifying protein, RAMP1, to function as a CGRP receptor [6].
  • Interestingly, the L94A mutant up-regulated surface expression of the receptor heterodimer to a greater degree than wild-type hRAMP1, thereby increasing CGRP binding and signaling [7].
  • Replacement of lysine 74 in rat RAMP1 with tryptophan (the homologous amino acid in the human receptor) resulted in a > or =100-fold increase in antagonist affinities, similar to the K(i) values for the human receptor [8].
  • Here we report that when expressed alone RAMP1 is retained inside the cells where it is found in the endoplasmic reticulum and the Golgi predominantly as a disulfide-linked homodimer [9].
  • Similarly, (125)I-CGRP selectively recognized the mature CRLR species upon co-expression with RAMP1, indicating that the glycosylation does not determine ligand-binding selectivity [10].

Biological context of RAMP1

  • Our results showed for the first time an up-regulation of RAMP1 and RAMP3 mRNAs and proteins in this model of cardiac failure [11].
  • Human RAMP1 was assigned to chromosome 2q36-->q37.1, RAMP2 to 17q12-->q21.1 and RAMP3 to 7p13-->p12 [12].
  • In rCRLR and hRAMP1 cotransfected cells, expressing predominantly CGRP binding sites, r betaCGRP, r alphaCGRP, and rADM induced CRE-luc with half-maximal effective concentration of 0.27 +/- 0.17 nM, 0.37 +/- 0.27 nM, and 1.4 +/- 0.9 nM, respectively [13].
  • The binding of CGRP and its ability to stimulate cAMP production were investigated in mutant and wild-type receptors after transient transfection into COS-7 cells with RAMP1 [14].
  • In contrast, whereas affinities for amylin and the CTs were similar for the RAMP 3-derived receptor, the efficacy of human CGRPalpha was markedly reduced (IC50, 1.12 +/- 0.45 x 10(-7) M; P <.05 versus RAMP 1) [15].

Anatomical context of RAMP1

  • CLR and RAMP1 were detected in perivascular nerves and arterial smooth muscle [16].
  • Here, transient expression of RAMP1 in rabbit aortic endothelial cells (RAEC) brought about stimulation of cAMP accumulation by human (h) alphaCGRP with an EC50 of 0.41 nM [1].
  • RAMP1 expression was specific to myometrial myocytes and vascular smooth muscle cells in uterine arteries [17].
  • Here, the function of the rat CRLR homologue (rCRLR) has been investigated in rat osteoblast-like UMR-106 cells and in COS-7 cells, in the absence and presence of hRAMP1 and -2 and combinations thereof [13].
  • 4. L6, SK-N-MC and Col-29 cells expressed mRNA for RAMP1 and RAMP2 but Rat-2 fibroblasts had only RAMP2 [18].

Associations of RAMP1 with chemical compounds


Physical interactions of RAMP1

  • Similarly, in HEK293 EBNA cells constitutively expressing RAMP1/CRLR receptor complex CGRP binding was remarkably inhibited [22].
  • The calcitonin-like receptor (CLR) and the calcitonin receptor (CTR) interact with receptor activity-modifying protein 1 (RAMP1) at the cell surface to form heterodimeric receptor complexes [23].

Regulatory relationships of RAMP1


Other interactions of RAMP1

  • Co-expression of RAMP1 and CRLR reconstituted a CGRP receptor that was able to activate the pheromone-signaling pathway with pharmacological properties similar to those observed previously in mammalian cells [25].
  • Detectable [125I]h alphaCGRP binding required the presence of hRAMP1, and the expression of CGRP binding sites was unaffected by coexpressed hRAMP2 [13].
  • Co-expression of RAMP3 together with RAMP1 reduced the maximal cAMP response to h alphaCGRP by 47% (P < 0.05) [1].
  • RAMP1 is transported to the cell surface together with the CRLR or the CT receptor [26].
  • Highest specific binding was observed when either RAMP1 or RAMP2/1 were cotransfected, indicating the importance of the RAMP transmembrane domain and/or carboxy terminus for the degree to which amylin receptors are expressed [27].

Analytical, diagnostic and therapeutic context of RAMP1

  • We have used semi-quantitative RT-PCR and Western-blot analysis to detect and quantify the mRNA and the protein of RAMP1 and RAMP3 in both atria and ventricles of failing hearts 6 months after aortic banding in rats [11].
  • In the present study significant molecular expression of CRLR concomitant with RAMP1, 2 and 3 were demonstrated in human meningeal, cerebral and temporal arteries by use of reverse transcriptase polymerase chain reactions (RT-PCR) [28].
  • Increases in CRLR and RAMP1 mRNA expressions occurred 4 h after treatment of VSMC with 10(-7) M dexamethasone and no change was found for RAMP2 mRNA [19].
  • Northern blot analyses revealed that the RAMP family genes are expressed in various tissues with different tissue specificity; RAMP1 is abundantly expressed in the brain, fat, thymus, and spleen, RAMP2 in the lung, spleen, fat, and aorta, while RAMP3 is most abundant in the kidney and lung [29].
  • We propose that RAMP1 gene transfer may be an effective strategy for increasing the effectiveness of CGRP-induced decrease in restenosis after aortic angioplasty [20].


  1. Receptor activity modifying proteins regulate the activity of a calcitonin gene-related peptide receptor in rabbit aortic endothelial cells. Muff, R., Leuthäuser, K., Bühlmann, N., Foord, S.M., Fischer, J.A., Born, W. FEBS Lett. (1998) [Pubmed]
  2. Decreased gene expression of adrenomedullin receptor in mouse lungs during sepsis. Ono, Y., Okano, I., Kojima, M., Okada, K., Kangawa, K. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  3. Role of adrenomedullin and its receptor system in renal pathophysiology. Mukoyama, M., Sugawara, A., Nagae, T., Mori, K., Murabe, H., Itoh, H., Tanaka, I., Nakao, K. Peptides (2001) [Pubmed]
  4. Decremental Ramp Atrial Extrastimuli Pacing Protocol for the Induction of Atrioventricular Nodal Re-entrant Tachycardia and Other Supraventricular Tachycardias. Kantharia, B.K., Padder, F.A., Kutalek, S.P. Pacing and clinical electrophysiology : PACE. (2006) [Pubmed]
  5. Randomized comparison between Ramp and Burst+ atrial antitachycardia pacing therapies in patients suffering from sinus node disease and atrial fibrillation and implanted with a DDDRP device. Gulizia, M., Mangiameli, S., Orazi, S., Chiarandà, G., Boriani, G., Piccione, G., DiGiovanni, N., Colletti, A., Puntrello, C., Butera, G., Vasco, C., Vaccaro, I., Scardace, G., Grammatico, A. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. (2006) [Pubmed]
  6. International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors. Poyner, D.R., Sexton, P.M., Marshall, I., Smith, D.M., Quirion, R., Born, W., Muff, R., Fischer, J.A., Foord, S.M. Pharmacol. Rev. (2002) [Pubmed]
  7. Identification of the human receptor activity-modifying protein 1 domains responsible for agonist binding specificity. Kuwasako, K., Kitamura, K., Nagoshi, Y., Cao, Y.N., Eto, T. J. Biol. Chem. (2003) [Pubmed]
  8. Receptor activity-modifying protein 1 determines the species selectivity of non-peptide CGRP receptor antagonists. Mallee, J.J., Salvatore, C.A., LeBourdelles, B., Oliver, K.R., Longmore, J., Koblan, K.S., Kane, S.A. J. Biol. Chem. (2002) [Pubmed]
  9. Agonist-promoted internalization of a ternary complex between calcitonin receptor-like receptor, receptor activity-modifying protein 1 (RAMP1), and beta-arrestin. Hilairet, S., Bélanger, C., Bertrand, J., Laperrière, A., Foord, S.M., Bouvier, M. J. Biol. Chem. (2001) [Pubmed]
  10. Protein-protein interaction and not glycosylation determines the binding selectivity of heterodimers between the calcitonin receptor-like receptor and the receptor activity-modifying proteins. Hilairet, S., Foord, S.M., Marshall, F.H., Bouvier, M. J. Biol. Chem. (2001) [Pubmed]
  11. Increased myocardial expression of RAMP1 and RAMP3 in rats with chronic heart failure. Cueille, C., Pidoux, E., de Vernejoul, M.C., Ventura-Clapier, R., Garel, J.M. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  12. Genomic structure and chromosome mapping of human and mouse RAMP genes. Derst, C., Engel, H., Grzeschik, K., Daut, J. Cytogenet. Cell Genet. (2000) [Pubmed]
  13. A receptor activity modifying protein (RAMP)2-dependent adrenomedullin receptor is a calcitonin gene-related peptide receptor when coexpressed with human RAMP1. Bühlmann, N., Leuthäuser, K., Muff, R., Fischer, J.A., Born, W. Endocrinology (1999) [Pubmed]
  14. A key role for transmembrane prolines in calcitonin receptor-like receptor agonist binding and signalling: implications for family B G-protein-coupled receptors. Conner, A.C., Hay, D.L., Simms, J., Howitt, S.G., Schindler, M., Smith, D.M., Wheatley, M., Poyner, D.R. Mol. Pharmacol. (2005) [Pubmed]
  15. Multiple amylin receptors arise from receptor activity-modifying protein interaction with the calcitonin receptor gene product. Christopoulos, G., Perry, K.J., Morfis, M., Tilakaratne, N., Gao, Y., Fraser, N.J., Main, M.J., Foord, S.M., Sexton, P.M. Mol. Pharmacol. (1999) [Pubmed]
  16. Localization of calcitonin receptor-like receptor and receptor activity modifying protein 1 in enteric neurons, dorsal root ganglia, and the spinal cord of the rat. Cottrell, G.S., Roosterman, D., Marvizon, J.C., Song, B., Wick, E., Pikios, S., Wong, H., Berthelier, C., Tang, Y., Sternini, C., Bunnett, N.W., Grady, E.F. J. Comp. Neurol. (2005) [Pubmed]
  17. Differential and cell-specific expression of calcitonin receptor-like receptor and receptor activity modifying proteins in the human uterus. Nikitenko, L.L., Brown, N.S., Smith, D.M., MacKenzie, I.Z., Bicknell, R., Rees, M.C. Mol. Hum. Reprod. (2001) [Pubmed]
  18. Comparison of the expression of calcitonin receptor-like receptor (CRLR) and receptor activity modifying proteins (RAMPs) with CGRP and adrenomedullin binding in cell lines. Choksi, T., Hay, D.L., Legon, S., Poyner, D.R., Hagner, S., Bloom, S.R., Smith, D.M. Br. J. Pharmacol. (2002) [Pubmed]
  19. Dexamethasone increases RAMP1 and CRLR mRNA expressions in human vascular smooth muscle cells. Frayon, S., Cueille, C., Gnidéhou, S., de Vernejoul, M.C., Garel, J.M. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  20. Calcitonin gene-related peptide receptor activation by receptor activity-modifying protein-1 gene transfer to vascular smooth muscle cells. Zhang, Z., Dickerson, I.M., Russo, A.F. Endocrinology (2006) [Pubmed]
  21. Aldosterone increases RAMP1 expression in mesenteric arteries from spontaneously hypertensive rats. Márquez-Rodas, I., Longo, F., Aras-López, R., Blanco-Rivero, J., Diéguez, E., Tejerina, T., Ferrer, M., Balfagón, G. Regul. Pept. (2006) [Pubmed]
  22. Glycosylation of human CRLR at Asn123 is required for ligand binding and signaling. Kamitani, S., Sakata, T. Biochim. Biophys. Acta (2001) [Pubmed]
  23. Identification and pharmacological characterization of domains involved in binding of CGRP receptor antagonists to the calcitonin-like receptor. Salvatore, C.A., Mallee, J.J., Bell, I.M., Zartman, C.B., Williams, T.M., Koblan, K.S., Kane, S.A. Biochemistry (2006) [Pubmed]
  24. Functional relevance of G-protein-coupled-receptor-associated proteins, exemplified by receptor-activity-modifying proteins (RAMPs). Fischer, J.A., Muff, R., Born, W. Biochem. Soc. Trans. (2002) [Pubmed]
  25. Functional expression of heteromeric calcitonin gene-related peptide and adrenomedullin receptors in yeast. Miret, J.J., Rakhilina, L., Silverman, L., Oehlen, B. J. Biol. Chem. (2002) [Pubmed]
  26. The transmembrane domain of receptor-activity-modifying protein 1 is essential for the functional expression of a calcitonin gene-related peptide receptor. Steiner, S., Muff, R., Gujer, R., Fischer, J.A., Born, W. Biochemistry (2002) [Pubmed]
  27. Multiple ramp domains are required for generation of amylin receptor phenotype from the calcitonin receptor gene product. Zumpe, E.T., Tilakaratne, N., Fraser, N.J., Christopoulos, G., Foord, S.M., Sexton, P.M. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  28. Expression of calcitonin receptor-like receptor and receptor-activity-modifying proteins in human cranial arteries. Sams, A., Jansen-Olesen, I. Neurosci. Lett. (1998) [Pubmed]
  29. Rat receptor-activity-modifying proteins (RAMPs) for adrenomedullin/CGRP receptor: cloning and upregulation in obstructive nephropathy. Nagae, T., Mukoyama, M., Sugawara, A., Mori, K., Yahata, K., Kasahara, M., Suganami, T., Makino, H., Fujinaga, Y., Yoshioka, T., Tanaka, I., Nakao, K. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
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