CALCRL

CALCRL
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3AQF, 3N7P, 3N7R, 3N7S, 4RWF
Identifiers
Aliases	CALCRL, CGRPR, CRLR, calcitonin receptor like receptor, LMPHM8
External IDs	OMIM: 114190; MGI: 1926944; HomoloGene: 21179; GeneCards: CALCRL; OMA:CALCRL - orthologs
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2q32.1 Start 187,341,964 bp[1] End 187,448,460 bp[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band 2|2 D Start 84,160,970 bp[2] End 84,255,755 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right lung upper lobe of left lung Achilles tendon gallbladder lower lobe of lung right coronary artery left coronary artery smooth muscle tissue subcutaneous adipose tissue popliteal artery Top expressed in left lung lobe right lung right lung lobe vas deferens iris atrioventricular valve carotid body genital tubercle endothelial cell of lymphatic vessel semi-lunar valve More reference expression data BioGPS More reference expression data
Gene ontology Molecular function G protein-coupled receptor activity calcitonin receptor activity signal transducer activity protein binding transmembrane signaling receptor activity adrenomedullin receptor activity calcitonin gene-related peptide receptor activity adrenomedullin binding Cellular component integral component of membrane endosome membrane plasma membrane integral component of plasma membrane endoplasmic reticulum lysosome cytoplasm adrenomedullin receptor complex CGRP receptor complex Biological process negative regulation of smooth muscle contraction G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger receptor internalization cellular response to sucrose stimulus development of the heart cell surface receptor signaling pathway angiogenesis positive regulation of cell population proliferation protein transport negative regulation of inflammatory response calcium ion transport signal transduction positive regulation of smooth muscle cell proliferation G protein-coupled receptor signaling pathway adenylate cyclase-activating G protein-coupled receptor signaling pathway calcitonin gene-related peptide receptor signaling pathway adrenomedullin receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10203 54598 Ensembl ENSG00000064989 ENSMUSG00000059588 UniProt Q16602 Q9R1W5 RefSeq (mRNA) NM_001271751 NM_005795 NM_001369434 NM_001369435 NM_018782 RefSeq (protein) NP_001258680 NP_005786 NP_001356363 NP_001356364 NP_061252 Location (UCSC) Chr 2: 187.34 – 187.45 Mb Chr 2: 84.16 – 84.26 Mb PubMed search [3] [4]
Wikidata
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]

Tissue distribution

RNA expression charts show highest expression in lung and adipose tissue in humans.^[6] Cell types that express the highest levels of CALCRL include oligodendrocyte precursor cells, endothelial cells, lymphatic endothelial cells, adipocytes, endometrial stromal cells, as well as dendritic cells.^[7]

Structure

The calcitonin receptor-like (CALCRL) protein is a class B G protein-coupled receptor (GPCR) characterized by seven transmembrane helices and a relatively large N-terminal extracellular domain (ECD) comprising 100–160 residues and three conserved disulfide bonds. CALCRL forms functional heterodimeric complexes with one of three single transmembrane receptor activity-modifying proteins (RAMPs), namely RAMP1, RAMP2, or RAMP3, which determine its ligand specificity. The extracellular domain of CALCRL consists of one α-helix, two antiparallel β-strands, five loop regions, and is stabilized by intramolecular disulfide bonds, which are crucial for ligand binding and specificity. The CALCRL/RAMP complex presents a unique ligand-binding pocket, enabling selective recognition of peptide agonists on the extracellular surface, which then triggers conformational changes in transmembrane helices to facilitate intracellular G-protein coupling and signal transduction.​^[8][9]

Function

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:^[10][11]

• with RAMP1: produces a CGRP receptor
• with RAMP2: produces an adrenomedullin (AM) receptor, designated AM₁^[12]
• with RAMP3: produces a dual CGRP/AM receptor designated AM₂

These receptors are linked to the G protein G_s,^[13] 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).^[14]

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.^[15] 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.^[16]

Adrenomedullin receptor

CALCRL binds Ramp2 to form the adrenomedullin receptor 1 (AM₁), while it binds Ramp3 to form adrenomedullin receptor 2 (AM₂). Adrenomedullin is a multifunctional 52 amino acid peptide widely expressed throughout the body. Its most prominent functions include regulation of blood pressure, endothelial barrier development and stability, and inflammation. Administration of adrenomedullin causes vasodilation and decreased blood pressure via binding to its receptors^[17].

Clinical significance

Calcitonin gene-related peptide receptor antagonists are FDA approved for the treatment of migraine. This includes Erenumab, Ubrogepant and Zavegepant.

Wounds

In wounds, CGRP receptors found in nerve cells deactivate the immune system, to prevent collateral damage in case of a clean wound (common case). In very preliminary research, nerve blockers like e.g. lidocaine or botox have been demonstrated to block CGRP cascade, thereby allowing immune system involvement and control of pathogens, resulting in complete control and recovery.^[18]

References

1. GRCh38: Ensembl release 89: ENSG00000064989 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000059588 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Aiyar N, Rand K, Elshourbagy NA, Zeng Z, Adamou JE, Bergsma DJ, et al. (May 1996). "A cDNA encoding the calcitonin gene-related peptide type 1 receptor". The Journal of Biological Chemistry. 271 (19): 11325–11329. doi:10.1074/jbc.271.19.11325. PMID 8626685.
6. "Tissue expression of CALCRL - Summary - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2025-11-03.
7. "Single cell type - CALCRL - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2025-11-03.
8. Barwell J, Gingell JJ, Watkins HA, Archbold JK, Poyner DR, Hay DL (May 2012). "Calcitonin and calcitonin receptor-like receptors: common themes with family B GPCRs?". British Journal of Pharmacology. 166 (1): 51–65. doi:10.1111/j.1476-5381.2011.01525.x. PMC 3415637. PMID 21649645.
9. PDB: 3N7S​; ter Haar E, Koth CM, Abdul-Manan N, Swenson L, Coll JT, Lippke JA, et al. (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): 1083–1093. doi:10.1016/j.str.2010.05.014. PMID 20826335.
10. McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, et al. (May 1998). "RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor". Nature. 393 (6683): 333–339. Bibcode:1998Natur.393..333M. doi:10.1038/30666. PMID 9620797. S2CID 4364526.
11. Foord SM, Marshall FH (May 1999). "RAMPs: accessory proteins for seven transmembrane domain receptors". Trends in Pharmacological Sciences. 20 (5): 184–187. doi:10.1016/S0165-6147(99)01347-4. PMID 10354609.
12. 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 Letters. 448 (1): 111–114. Bibcode:1999FEBSL.448..111K. doi:10.1016/S0014-5793(99)00358-0. PMID 10217420. S2CID 23729715.
13. "Receptor properties". SenseLab Project: Membrane properties resource. Yale University. Archived from the original on 2009-02-28. Retrieved 2008-09-28.
14. Arulmani U, Maassenvandenbrink A, Villalón CM, Saxena PR (October 2004). "Calcitonin gene-related peptide and its role in migraine pathophysiology". European Journal of Pharmacology. 500 (1–3): 315–330. doi:10.1016/j.ejphar.2004.07.035. PMID 15464043.
15. Weston C, Winfield I, Harris M, Hodgson R, Shah A, Dowell SJ, et al. (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 5063977. PMID 27566546.
16. Woolley MJ, Reynolds CA, Simms J, Walker CS, Mobarec JC, Garelja ML, et al. (October 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. 142: 96–110. doi:10.1016/j.bcp.2017.07.005. PMC 5609567. PMID 28705698.
17. Geven C, Kox M, Pickkers P (2018-02-19). "Adrenomedullin and Adrenomedullin-Targeted Therapy As Treatment Strategies Relevant for Sepsis". Frontiers in Immunology. 9 292. doi:10.3389/fimmu.2018.00292. PMC 5827550. PMID 29520277.
18. "How the germ behind flesh-eating disease hijacks neurons to avoid immune destruction".

Further reading

• Born W, Muff R, Fischer JA (April 2002). "Functional interaction of G protein-coupled receptors of the adrenomedullin peptide family with accessory receptor-activity-modifying proteins (RAMP)". Microscopy Research and Technique. 57 (1): 14–22. doi:10.1002/jemt.10051. PMID 11921352. S2CID 20459079.
• Yallampalli C, Chauhan M, Thota CS, Kondapaka S, Wimalawansa SJ (August 2002). "Calcitonin gene-related peptide in pregnancy and its emerging receptor heterogeneity". Trends in Endocrinology and Metabolism. 13 (6): 263–269. doi:10.1016/s1043-2760(02)00563-5. PMID 12128288. S2CID 28476322.
• Foord SM, Craig RK (December 1987). "Isolation and characterisation of a human calcitonin-gene-related-peptide receptor". European Journal of Biochemistry. 170 (1–2): 373–379. 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): 975–986. doi:10.1016/0196-9781(85)90331-6. PMID 3001670. S2CID 19435035.
• Flühmann B, Muff R, Hunziker W, Fischer JA, Born W (January 1995). "A human orphan calcitonin receptor-like structure". Biochemical and Biophysical Research Communications. 206 (1): 341–347. Bibcode:1995BBRC..206..341F. doi:10.1006/bbrc.1995.1047. PMID 7818539.
• Aiyar N, Rand K, Elshourbagy NA, Zeng Z, Adamou JE, Bergsma DJ, et al. (May 1996). "A cDNA encoding the calcitonin gene-related peptide type 1 receptor". The Journal of Biological Chemistry. 271 (19): 11325–11329. doi:10.1074/jbc.271.19.11325. PMID 8626685.
• McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, et al. (May 1998). "RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor". Nature. 393 (6683): 333–339. Bibcode:1998Natur.393..333M. doi:10.1038/30666. PMID 9620797. S2CID 4364526.
• Sams A, Jansen-Olesen I (December 1998). "Expression of calcitonin receptor-like receptor and receptor-activity-modifying proteins in human cranial arteries". Neuroscience Letters. 258 (1): 41–44. doi:10.1016/S0304-3940(98)00844-1. PMID 9876047. S2CID 371196.
• 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 Letters. 448 (1): 111–114. Bibcode:1999FEBSL.448..111K. doi:10.1016/S0014-5793(99)00358-0. PMID 10217420. S2CID 23729715.
• Aldecoa A, Gujer R, Fischer JA, Born W (April 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 Letters. 471 (2–3): 156–160. Bibcode:2000FEBSL.471..156A. doi:10.1016/S0014-5793(00)01387-9. PMID 10767413. S2CID 32098863.
• Frayon S, Cueille C, Gnidéhou S, de Vernejoul MC, Garel JM (April 2000). "Dexamethasone increases RAMP1 and CRLR mRNA expressions in human vascular smooth muscle cells". Biochemical and Biophysical Research Communications. 270 (3): 1063–1067. Bibcode:2000BBRC..270.1063F. doi:10.1006/bbrc.2000.2552. PMID 10772950.
• Kuwasako K, Shimekake Y, Masuda M, Nakahara K, Yoshida T, Kitaura M, et al. (September 2000). "Visualization of the calcitonin receptor-like receptor and its receptor activity-modifying proteins during internalization and recycling". The Journal of Biological Chemistry. 275 (38): 29602–29609. doi:10.1074/jbc.M004534200. PMID 10882736.
• Evans BN, Rosenblatt MI, Mnayer LO, Oliver KR, Dickerson IM (October 2000). "CGRP-RCP, a novel protein required for signal transduction at calcitonin gene-related peptide and adrenomedullin receptors". The Journal of Biological Chemistry. 275 (40): 31438–31443. doi:10.1074/jbc.M005604200. PMID 10903324.
• Hilairet S, Foord SM, Marshall FH, Bouvier M (August 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. 276 (31): 29575–29581. doi:10.1074/jbc.M102722200. PMID 11387328.
• Kamitani S, Sakata T (May 2001). "Glycosylation of human CRLR at Asn123 is required for ligand binding and signaling". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1539 (1–2): 131–139. doi:10.1016/S0167-4889(01)00100-8. PMID 11389975.
• Nikitenko LL, Brown NS, Smith DM, MacKenzie IZ, Bicknell R, Rees MC (July 2001). "Differential and cell-specific expression of calcitonin receptor-like receptor and receptor activity modifying proteins in the human uterus". Molecular Human Reproduction. 7 (7): 655–664. doi:10.1093/molehr/7.7.655. PMID 11420389.
• Hilairet S, Bélanger C, Bertrand J, Laperrière A, Foord SM, Bouvier M (November 2001). "Agonist-promoted internalization of a ternary complex between calcitonin receptor-like receptor, receptor activity-modifying protein 1 (RAMP1), and beta-arrestin". The Journal of Biological Chemistry. 276 (45): 42182–42190. doi:10.1074/jbc.M107323200. PMID 11535606.
• Aiyar N, Disa J, Pullen M, Nambi P (August 2001). "Receptor activity modifying proteins interaction with human and porcine calcitonin receptor-like receptor (CRLR) in HEK-293 cells". Molecular and Cellular Biochemistry. 224 (1–2): 123–133. doi:10.1023/A:1011907328682. PMID 11693189. S2CID 26037173.
• Hagner S, Haberberger RV, Overkamp D, Hoffmann R, Voigt KH, McGregor GP (January 2002). "Expression and distribution of calcitonin receptor-like receptor in human hairy skin". Peptides. 23 (1): 109–116. doi:10.1016/S0196-9781(01)00586-1. PMID 11814625. S2CID 6936664.
• Hill HE, Pioszak AA (March 2013). "Bacterial expression and purification of a heterodimeric adrenomedullin receptor extracellular domain complex using DsbC-assisted disulfide shuffling". Protein Expression and Purification. 88 (1): 107–113. doi:10.1016/j.pep.2012.11.019. PMC 3568255. PMID 23247088.

External links

• "Calcitonin receptors: CALCRL". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
• calcitonin+receptor-like+receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• CALCRL human gene location in the UCSC Genome Browser.
• CALCRL human gene details in the UCSC Genome Browser.