CALCRL

Calcitonin receptor-like
Crystallographic structure of the ectodomain complex of the CGRP type 1 receptor and RAMP1.[1]
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 3AQF​, 3N7P​, 3N7R​, 3N7S​, 4RWF​, 4RWG​
Identifiers
Symbols	CALCRL ; CGRPR; CRLR
External IDs	OMIM: 114190 MGI: 1926944 HomoloGene: 21179 IUPHAR: 47 ChEMBL: 3798 GeneCards: CALCRL Gene
Gene ontology Molecular function • adrenomedullin receptor activity • calcitonin gene-related peptide receptor activity • G-protein coupled receptor activity • calcitonin receptor activity • protein binding • protein transporter activity Cellular component • lysosome • endosome • endoplasmic reticulum • plasma membrane • integral component of plasma membrane Biological process • angiogenesis • cAMP biosynthetic process • calcium ion transport • cell surface receptor signaling pathway • G-protein coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger • adenylate cyclase-activating G-protein coupled receptor signaling pathway • heart development • protein transport • positive regulation of cAMP biosynthetic process • receptor internalization • negative regulation of smooth muscle contraction • positive regulation of smooth muscle cell proliferation • negative regulation of inflammatory response • cellular response to sucrose stimulus Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	10203	54598
Ensembl	ENSG00000064989	ENSMUSG00000059588
UniProt	Q16602	Q9R1W5
RefSeq (mRNA)	NM_001271751	NM_018782
RefSeq (protein)	NP_001258680	NP_061252
Location (UCSC)	Chr 2: 187.34 – 187.45 Mb	Chr 2: 84.33 – 84.43 Mb
PubMed search

Calcitonin receptor-like (CALCRL), also known as the calcitonin receptor-like receptor (CRLR), is a human protein.^[2]

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:^[3][4]

• with RAMP1: produces a CGRP receptor
• with RAMP2: produces an adrenomedullin (AM) receptor, designated AM₁^[5]
• with RAMP3: produces a dual CGRP/AM receptor designated AM₂

These receptors are linked to the G protein G_s,^[6] which activates adenylate cyclase and activation results in the generation of intracellular cyclic adenosine monophosphate (cAMP).

Structure

CALCRL associated with RAMP 1 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.^[1]

Clinical significance

These G-protein coupled receptor (GPCRs) proteins play an important role in pharmaceutical targets. Many drugs used today alter the GPCR signaling pathways,^[1] notably calcitonin gene-related peptide receptor antagonists that are under investigation for the treatment of migraine.

References

1. PDB: 3N7S​; ter Haar E, Koth CM, Abdul-Manan N, Swenson L, Coll JT, Lippke JA, Lepre CA, Garcia-Guzman M, Moore JM (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.
2. 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.
3. 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.
4. 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.
5. 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.
6. "Receptor properties". SenseLab Project: Membrane properties resource. Yale University. Retrieved 2008-09-28.

Further reading

• 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. 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 US 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.