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Gene Review

CALCRL  -  calcitonin receptor-like

Homo sapiens

Synonyms: CGRP type 1 receptor, CGRPR, CRLR, Calcitonin gene-related peptide type 1 receptor, Calcitonin receptor-like receptor
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Disease relevance of CALCRL


High impact information on CALCRL


Chemical compound and disease context of CALCRL


Biological context of CALCRL


Anatomical context of CALCRL

  • The sequence is unrelated to consensus endoplasmic reticulum retention/retrieval motives and overridden by the presence of the hCRLR [19].
  • 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 [20].
  • CLR and RAMP1 were detected in perivascular nerves and arterial smooth muscle [20].
  • MATERIALS AND METHODS: Expression of CGRP receptor components on CD34(+) cells, peripheral blood granulocytes, and in vitro differentiated CD34(+) cells was analyzed at the mRNA level and by measuring the signaling capacity of the receptor [21].
  • CLR was detected at low levels in the soma of enteric, dorsal root ganglia (DRG), and spinal neurons [20].

Associations of CALCRL with chemical compounds

  • Cysteine residues in the extracellular loops of hCRLR and in the extracellular domain of hRAMP2 thus appear to play distinct roles in the cell surface expression and function of the receptor heterodimer [22].
  • Whichever RAMP protein was co-expressing with CRLR, the ligand binding was sensitive to tunicamycin [23].
  • This internalization was strongly inhibited by hypertonic medium (0.45 m sucrose) and paralleled localization of rhodamine-labeled transferrin, suggesting that CRLR endocytosis occurred predominantly through a clathrin-dependent pathway [24].
  • Furthermore, CGRP-induced relaxation of placental vessels are inhibited by a CGRP receptor antagonist (CGRP8-37), ATP-sensitive potassium (KATP) channel blocker (glybenclamide), and cAMP-dependent protein kinase A inhibitor (Rp-cAMPS) and partially inhibited by a nitric oxide inhibitor (Nomega-nitro-l-arginine methyl ester) [25].
  • CRLR mRNA levels were half-reduced with the two lowest doses of dexamethasone (10(-10) and 10(-9) M), but increased from 10(-8) to 10(-7) M [26].

Physical interactions of CALCRL

  • By contrast, deletion of the C-tail from hRAMP2 disrupted transport of hCRLR to the cell surface, resulting in significant reductions in (125)I-hAM binding and evoked cAMP accumulation [27].
  • RAMP 1-transported CRLR is a calcitonin gene-related peptide (CGRP) receptor [28].
  • RAMP2- and RAMP3-transported CRLR receptors act as AM-specific receptors [29].
  • Analysis of CRLR mutants in which Gln was substituted for selected Asn residues showed that glycosylation of Asn123 is required for both the binding of adrenomedullin and the transduction of its signal [23].
  • Similarly, in HEK293 EBNA cells constitutively expressing RAMP1/CRLR receptor complex CGRP binding was remarkably inhibited [23].

Regulatory relationships of CALCRL

  • CRLR, initially classed as an orphan receptor, is a CGRP receptor when co-expressed with RAMP1 [30].
  • TNF-alpha induced time- and dose-dependent decreases in the expression of CRLR and RAMP1/2 mRNAs, thereby diminishing AM-evoked cAMP production [31].
  • 4. h-alpha CGRP(8-37) and BIBN4096BS concentration-dependently inhibited cAMP formation evoked by CGRP receptor agonists [32].
  • Aim: To determine whether CRLR is expressed in human gliomas and the probable cellular targets of adrenomedullin [33].
  • CGRP-mediated JNK-activation was inhibited by CGRP receptor antagonist, CGRP8-37, confirming that this is a receptor-mediated event [34].

Other interactions of CALCRL


Analytical, diagnostic and therapeutic context of CALCRL


  1. Adrenomedullin is expressed in pancreatic cancer and stimulates cell proliferation and invasion in an autocrine manner via the adrenomedullin receptor, ADMR. Ramachandran, V., Arumugam, T., Hwang, R.F., Greenson, J.K., Simeone, D.M., Logsdon, C.D. Cancer Res. (2007) [Pubmed]
  2. Role of the N-terminal domain of the calcitonin receptor-like receptor in ligand binding. Chauhan, M., Rajarathnam, K., Yallampalli, C. Biochemistry (2005) [Pubmed]
  3. The CGRP receptor can couple via pertussis toxin sensitive and insensitive G proteins. Main, M.J., Brown, J., Brown, S., Fraser, N.J., Foord, S.M. FEBS Lett. (1998) [Pubmed]
  4. Concomitant expression of adrenomedullin and its receptor components in rat adipose tissues. Fukai, N., Yoshimoto, T., Sugiyama, T., Ozawa, N., Sato, R., Shichiri, M., Hirata, Y. Am. J. Physiol. Endocrinol. Metab. (2005) [Pubmed]
  5. Adrenomedullin enhances invasion by trophoblast cell lines. Zhang, X., Green, K.E., Yallampalli, C., Dong, Y.L. Biol. Reprod. (2005) [Pubmed]
  6. Vascular actions of calcitonin gene-related peptide and adrenomedullin. Brain, S.D., Grant, A.D. Physiol. Rev. (2004) [Pubmed]
  7. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. McLatchie, L.M., Fraser, N.J., Main, M.J., Wise, A., Brown, J., Thompson, N., Solari, R., Lee, M.G., Foord, S.M. Nature (1998) [Pubmed]
  8. Rectal instillation of butyrate provides a novel clinically relevant model of noninflammatory colonic hypersensitivity in rats. Bourdu, S., Dapoigny, M., Chapuy, E., Artigue, F., Vasson, M.P., Dechelotte, P., Bommelaer, G., Eschalier, A., Ardid, D. Gastroenterology (2005) [Pubmed]
  9. The perils of using the human genome sequence: lessons from CALCRL. Conner, A.C., Poyner, D.R. Trends Pharmacol. Sci. (2001) [Pubmed]
  10. 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]
  11. Calcitonin gene-related peptide (CGRP) increases intracellular free Ca2+ concentrations but not cyclic AMP formation in CGRP receptor-positive osteosarcoma cells (OHS-4). Drissi, H., Lieberherr, M., Hott, M., Marie, P.J., Lasmoles, F. Cytokine (1999) [Pubmed]
  12. CGRP receptor antagonists: a new choice for acute treatment of migraine? Durham, P.L. Current opinion in investigational drugs (London, England : 2000) (2004) [Pubmed]
  13. Involvement of endothelial cell-derived CGRP in heat stress-induced protection of endothelial function. Ye, F., Deng, P.Y., Li, D., Luo, D., Li, N.S., Deng, S., Deng, H.W., Li, Y.J. Vascul. Pharmacol. (2007) [Pubmed]
  14. 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]
  15. Intermedin is a calcitonin/calcitonin gene-related peptide family peptide acting through the calcitonin receptor-like receptor/receptor activity-modifying protein receptor complexes. Roh, J., Chang, C.L., Bhalla, A., Klein, C., Hsu, S.Y. J. Biol. Chem. (2004) [Pubmed]
  16. 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]
  17. Receptor activity modifying proteins interaction with human and porcine calcitonin receptor-like receptor (CRLR) in HEK-293 cells. Aiyar, N., Disa, J., Pullen, M., Nambi, P. Mol. Cell. Biochem. (2001) [Pubmed]
  18. Human skin keratinocytes and fibroblasts express adrenomedullin and its receptors, and adrenomedullin enhances their growth in vitro by stimulating proliferation and inhibiting apoptosis. Albertin, G., Carraro, G., Parnigotto, P.P., Conconi, M.T., Ziolkowska, A., Malendowicz, L.K., Nussdorfer, G.G. Int. J. Mol. Med. (2003) [Pubmed]
  19. 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]
  20. 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]
  21. Regulation and function of the CGRP receptor complex in human granulopoiesis. Harzenetter, M.D., Keller, U., Beer, S., Riedl, C., Peschel, C., Holzmann, B. Exp. Hematol. (2002) [Pubmed]
  22. The function of extracellular cysteines in the human adrenomedullin receptor. Kuwasako, K., Kitamura, K., Uemura, T., Nagoshi, Y., Kato, J., Eto, T. Hypertens. Res. (2003) [Pubmed]
  23. Glycosylation of human CRLR at Asn123 is required for ligand binding and signaling. Kamitani, S., Sakata, T. Biochim. Biophys. Acta (2001) [Pubmed]
  24. Visualization of the calcitonin receptor-like receptor and its receptor activity-modifying proteins during internalization and recycling. Kuwasako, K., Shimekake, Y., Masuda, M., Nakahara, K., Yoshida, T., Kitaura, M., Kitamura, K., Eto, T., Sakata, T. J. Biol. Chem. (2000) [Pubmed]
  25. Involvement of calcitonin gene-related peptide in control of human fetoplacental vascular tone. Dong, Y.L., Vegiraju, S., Chauhan, M., Gangula, P.R., Hankins, G.D., Goodrum, L., Yallampalli, C. Am. J. Physiol. Heart Circ. Physiol. (2004) [Pubmed]
  26. 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]
  27. Functions of the cytoplasmic tails of the human receptor activity-modifying protein components of calcitonin gene-related peptide and adrenomedullin receptors. Kuwasako, K., Cao, Y.N., Chu, C.P., Iwatsubo, S., Eto, T., Kitamura, K. J. Biol. Chem. (2006) [Pubmed]
  28. 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]
  29. 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]
  30. 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]
  31. Tumor necrosis factor-alpha downregulates adrenomedullin receptors in human coronary artery smooth muscle cells. Nagoshi, Y., Kuwasako, K., Cao, Y.N., Imamura, T., Kitamura, K., Eto, T. Peptides (2004) [Pubmed]
  32. Characterization of calcitonin gene-related peptide (CGRP) receptors and their receptor-activity-modifying proteins (RAMPs) in human brain microvascular and astroglial cells in culture. Moreno, M.J., Terrón, J.A., Stanimirovic, D.B., Doods, H., Hamel, E. Neuropharmacology (2002) [Pubmed]
  33. The immunohistochemical expression of calcitonin receptor-like receptor (CRLR) in human gliomas. Benes, L., Kappus, C., McGregor, G.P., Bertalanffy, H., Mennel, H.D., Hagner, S. J. Clin. Pathol. (2004) [Pubmed]
  34. Involvement of cAMP-dependent protein kinase and pertussis toxin-sensitive G-proteins in CGRP mediated JNK activation in human neuroblastoma cell line. Disa, J., Parameswaran, N., Nambi, P., Aiyar, N. Neuropeptides (2000) [Pubmed]
  35. Receptor autoradiography as mean to explore the possible functional relevance of neuropeptides: focus on new agonists and antagonists to study natriuretic peptides, neuropeptide Y and calcitonin gene-related peptides. Dumont, Y., Chabot, J.G., Quirion, R. Peptides (2004) [Pubmed]
  36. The calcitonin receptor-like receptor/receptor activity-modifying protein 1 heterodimer can function as a calcitonin gene-related peptide-(8-37)-sensitive adrenomedullin receptor. Nagoshi, Y., Kuwasako, K., Ito, K., Uemura, T., Kato, J., Kitamura, K., Eto, T. Eur. J. Pharmacol. (2002) [Pubmed]
  37. Sequencing of a calcitonin receptor-like receptor in salmon Oncorhynchus gorbuscha. Functional studies using the human receptor activity-modifying proteins. Pidoux, E., Cressent, M. Gene (2002) [Pubmed]
  38. Calcitonin receptor-like receptor: identification and distribution in human peripheral tissues. Hagner, S., Stahl, U., Knoblauch, B., McGregor, G.P., Lang, R.E. Cell Tissue Res. (2002) [Pubmed]
  39. A critical role for the short intracellular C terminus in receptor activity-modifying protein function. Udawela, M., Christopoulos, G., Morfis, M., Christopoulos, A., Ye, S., Tilakaratne, N., Sexton, P.M. Mol. Pharmacol. (2006) [Pubmed]
  40. Molecular cloning and pharmacological characterization of bovine calcitonin receptor-like receptor from bovine aortic endothelial cells. Aiyar, N., Disa, J., Ao, Z., Xu, D., Surya, A., Pillarisetti, K., Parameswaran, N., Gupta, S.K., Douglas, S.A., Nambi, P. Biochem. Pharmacol. (2002) [Pubmed]
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