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Available structures
PDB Ortholog search: PDBe RCSB
Aliases CALCRL, CGRPR, CRLR, calcitonin receptor like receptor
External IDs MGI: 1926944 HomoloGene: 21179 GeneCards: CALCRL
Gene location (Human)
Chromosome 2 (human)
Chr. Chromosome 2 (human)[1]
Chromosome 2 (human)
Genomic location for CALCRL
Genomic location for CALCRL
Band 2q32.1 Start 187,343,129 bp[1]
End 187,448,460 bp[1]
RNA expression pattern
PBB GE CALCRL 206331 at fs.png

PBB GE CALCRL 210815 s at fs.png
More reference expression data
Species Human Mouse
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC) Chr 2: 187.34 – 187.45 Mb Chr 2: 84.33 – 84.43 Mb
PubMed search [3] [4]
View/Edit Human View/Edit Mouse

Calcitonin receptor-like (CALCRL), also known as the calcitonin receptor-like receptor (CRLR), is a human protein; it is a receptor for calcitonin gene-related peptide.[5]


The protein encoded by the CALCRL gene is a G protein-coupled receptor related to the calcitonin receptor. CALCRL is linked to one of three single transmembrane domain receptor activity-modifying proteins (RAMPs) that are essential for functional activity.

The association of CALCRL with different RAMP proteins produces different receptors:[6][7]

These receptors are linked to the G protein Gs,[9] which activates adenylate cyclase and activation results in the generation of intracellular cyclic adenosine monophosphate (cAMP).

CGRP receptors are found throughout the body, suggesting that the protein may modulate a variety of physiological functions in all major systems (e.g., respiratory, endocrine, gastrointestinal, immune, and cardiovascular).[10]


In wounds, CGRP receptors found in nerve cells deactivate the immune system, to prevent collateral damage in case of a clean wound (common case). However, when a wily pathogen such as those causing necrotizing fasciitis are involved, this is the wrong response; in very preliminary research, nerve blockers like botox have been demonstrated to block CGRP cascade, thereby allowing immune system involvement and control of pathogens, resulting in complete control and recovery.[11]


CALCRL associated with RAMP1 produces the CGRP receptor which is a trans-membrane protein receptor that is made up of four chains. Two of the four chains contain unique sequences, it is a heterodimer protein composed of two polypeptide chains differing in composition of their amino acid residues. The sequence reveals multiple hydrophobic and hydrophilic regions throughout the four chains in the protein.[12]

The CGRP family of receptors including CALCRL can couple to G-protein Gαs, Gαi and Gαq subunits to transduce their signals. Furthermore binding of ligands to CALCRL can bias coupling to these G-protein.[13] Peptide agonist bind to the extracellular loops of CALCRL, this binding in turn causes TM5 (transmembrane helix 5) and TM6 to pivot around TM3 which in turn facilitates Gαs binding.[14]

adrenomedullin receptor[edit]


The RNA expression charts show a high level in fetal lung.

Clinical significance[edit]

As a drug target[edit]

calcitonin gene-related peptide receptor antagonists are under investigation for the treatment of migraine.[15][16]


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000064989 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000059588 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". 
  4. ^ "Mouse PubMed Reference:". 
  5. ^ Aiyar N, Rand K, Elshourbagy NA, Zeng Z, Adamou JE, Bergsma DJ, Li Y (May 1996). "A cDNA encoding the calcitonin gene-related peptide type 1 receptor". J. Biol. Chem. 271 (19): 11325–9. doi:10.1074/jbc.271.19.11325. PMID 8626685. 
  6. ^ McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, Solari R, Lee MG, Foord SM (May 1998). "RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor". Nature. 393 (6683): 333–9. doi:10.1038/30666. PMID 9620797. 
  7. ^ Foord SM, Marshall FH (May 1999). "RAMPs: accessory proteins for seven transmembrane domain receptors". Trends Pharmacol. Sci. 20 (5): 184–7. doi:10.1016/S0165-6147(99)01347-4. PMID 10354609. 
  8. ^ Kamitani S, Asakawa M, Shimekake Y, Kuwasako K, Nakahara K, Sakata T (April 1999). "The RAMP2/CRLR complex is a functional adrenomedullin receptor in human endothelial and vascular smooth muscle cells". FEBS Lett. 448 (1): 111–4. doi:10.1016/S0014-5793(99)00358-0. PMID 10217420. 
  9. ^ "Receptor properties". SenseLab Project: Membrane properties resource. Yale University. Retrieved 2008-09-28. 
  10. ^ Arulmani, U.; et al. (2004). "Calcitonin gene-related peptide and its role in migraine pathophysiology". Eur J Pharmacol. 500 (1–3): 315–30. doi:10.1016/j.ejphar.2004.07.035. PMID 15464043. 
  11. ^
  12. ^ PDB: 3N7S​; ter Haar E, Koth CM, Abdul-Manan N, Swenson L, Coll JT, Lippke JA, Lepre CA, Garcia-Guzman M, Moore JM (September 2010). "Crystal structure of the ectodomain complex of the CGRP receptor, a class-B GPCR, reveals the site of drug antagonism". Structure. 18 (9): 1083–93. doi:10.1016/j.str.2010.05.014. PMID 20826335. 
  13. ^ Weston C, Winfield I, Harris M, Hodgson R, Shah A, Dowell SJ, Mobarec JC, Woodlock DA, Reynolds CA, Poyner DR, Watkins HA, Ladds G (October 2016). "Receptor Activity-modifying Protein-directed G Protein Signaling Specificity for the Calcitonin Gene-related Peptide Family of Receptors". The Journal of Biological Chemistry. 291 (42): 21925–21944. doi:10.1074/jbc.M116.751362. PMC 5063977Freely accessible. PMID 27566546. 
  14. ^ Woolley MJ, Reynolds CA, Simms J, Walker CS, Mobarec JC, Garelja ML, Conner AC, Poyner DR, Hay DL (July 2017). "Receptor activity-modifying protein dependent and independent activation mechanisms in the coupling of calcitonin gene-related peptide and adrenomedullin receptors to Gs". Biochemical Pharmacology. 17: 30482–3. doi:10.1016/j.bcp.2017.07.005. PMC 5609567Freely accessible. PMID 28705698. 
  15. ^ Dunn L, Deo P (February 24, 2017). "New Drugs May Stop Migraines Before They Start". NBC News. Retrieved February 24, 2017. 
  16. ^ Edvinsson L, Warfvinge K (2013). "CGRP receptor antagonism and migraine therapy". Current Protein & Peptide Science. 14 (5): 386–92. doi:10.2174/13892037113149990055. PMID 23745702. 

Further reading[edit]

  • Born W, Muff R, Fischer JA (2002). "Functional interaction of G protein-coupled receptors of the adrenomedullin peptide family with accessory receptor-activity-modifying proteins (RAMP)". Microsc. Res. Tech. 57 (1): 14–22. doi:10.1002/jemt.10051. PMID 11921352. 
  • Yallampalli C, Chauhan M, Thota CS, et al. (2003). "Calcitonin gene-related peptide in pregnancy and its emerging receptor heterogeneity". Trends Endocrinol. Metab. 13 (6): 263–9. doi:10.1016/s1043-2760(02)00563-5. PMID 12128288. 
  • Foord SM, Craig RK (1988). "Isolation and characterisation of a human calcitonin-gene-related-peptide receptor". Eur. J. Biochem. 170 (1–2): 373–9. doi:10.1111/j.1432-1033.1987.tb13710.x. PMID 2826160. 
  • Skofitsch G, Jacobowitz DM (1986). "Autoradiographic distribution of 125I calcitonin gene-related peptide binding sites in the rat central nervous system". Peptides. 6 (5): 975–86. doi:10.1016/0196-9781(85)90331-6. PMID 3001670. 
  • Flühmann B, Muff R, Hunziker W, et al. (1995). "A human orphan calcitonin receptor-like structure". Biochem. Biophys. Res. Commun. 206 (1): 341–7. doi:10.1006/bbrc.1995.1047. PMID 7818539. 
  • Aiyar N, Rand K, Elshourbagy NA, et al. (1996). "A cDNA encoding the calcitonin gene-related peptide type 1 receptor". J. Biol. Chem. 271 (19): 11325–9. doi:10.1074/jbc.271.19.11325. PMID 8626685. 
  • McLatchie LM, Fraser NJ, Main MJ, et al. (1998). "RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor". Nature. 393 (6683): 333–9. doi:10.1038/30666. PMID 9620797. 
  • Sams A, Jansen-Olesen I (1999). "Expression of calcitonin receptor-like receptor and receptor-activity-modifying proteins in human cranial arteries". Neurosci. Lett. 258 (1): 41–4. doi:10.1016/S0304-3940(98)00844-1. PMID 9876047. 
  • Kamitani S, Asakawa M, Shimekake Y, et al. (1999). "The RAMP2/CRLR complex is a functional adrenomedullin receptor in human endothelial and vascular smooth muscle cells". FEBS Lett. 448 (1): 111–4. doi:10.1016/S0014-5793(99)00358-0. PMID 10217420. 
  • Aldecoa A, Gujer R, Fischer JA, Born W (2000). "Mammalian calcitonin receptor-like receptor/receptor activity modifying protein complexes define calcitonin gene-related peptide and adrenomedullin receptors in Drosophila Schneider 2 cells". FEBS Lett. 471 (2–3): 156–60. doi:10.1016/S0014-5793(00)01387-9. PMID 10767413. 
  • Frayon S, Cueille C, Gnidéhou S, et al. (2000). "Dexamethasone increases RAMP1 and CRLR mRNA expressions in human vascular smooth muscle cells". Biochem. Biophys. Res. Commun. 270 (3): 1063–7. doi:10.1006/bbrc.2000.2552. PMID 10772950. 
  • Kuwasako K, Shimekake Y, Masuda M, et al. (2000). "Visualization of the calcitonin receptor-like receptor and its receptor activity-modifying proteins during internalization and recycling". J. Biol. Chem. 275 (38): 29602–9. doi:10.1074/jbc.M004534200. PMID 10882736. 
  • Evans BN, Rosenblatt MI, Mnayer LO, et al. (2000). "CGRP-RCP, a novel protein required for signal transduction at calcitonin gene-related peptide and adrenomedullin receptors". J. Biol. Chem. 275 (40): 31438–43. doi:10.1074/jbc.M005604200. PMID 10903324. 
  • Hilairet S, Foord SM, Marshall FH, Bouvier M (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". J. Biol. Chem. 276 (31): 29575–81. doi:10.1074/jbc.M102722200. PMID 11387328. 
  • Kamitani S, Sakata T (2001). "Glycosylation of human CRLR at Asn123 is required for ligand binding and signaling". Biochim. Biophys. Acta. 1539 (1–2): 131–9. doi:10.1016/S0167-4889(01)00100-8. PMID 11389975. 
  • Nikitenko LL, Brown NS, Smith DM, et al. (2001). "Differential and cell-specific expression of calcitonin receptor-like receptor and receptor activity modifying proteins in the human uterus". Mol. Hum. Reprod. 7 (7): 655–64. doi:10.1093/molehr/7.7.655. PMID 11420389. 
  • Hilairet S, Bélanger C, Bertrand J, et al. (2001). "Agonist-promoted internalization of a ternary complex between calcitonin receptor-like receptor, receptor activity-modifying protein 1 (RAMP1), and beta-arrestin". J. Biol. Chem. 276 (45): 42182–90. doi:10.1074/jbc.M107323200. PMID 11535606. 
  • Aiyar N, Disa J, Pullen M, Nambi P (2002). "Receptor activity modifying proteins interaction with human and porcine calcitonin receptor-like receptor (CRLR) in HEK-293 cells". Mol. Cell. Biochem. 224 (1–2): 123–33. doi:10.1023/A:1011907328682. PMID 11693189. 
  • Hagner S, Haberberger RV, Overkamp D, et al. (2002). "Expression and distribution of calcitonin receptor-like receptor in human hairy skin". Peptides. 23 (1): 109–16. doi:10.1016/S0196-9781(01)00586-1. PMID 11814625. 
  • Hill H, Pioszak A (2013). "Bacterial expression and purification of a heterodimeric adrenomedullin receptor extracellular domain complex using DsbC-assisted disulfide shuffling". Protein Expr Purif. 88 (1): 107–13. doi:10.1016/j.pep.2012.11.019. PMC 3568255Freely accessible. PMID 23247088. 

External links[edit]