CALCRL explained

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.^[1]

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:^{[2] [3]}

• with RAMP1: produces a CGRP receptor
• with RAMP2: produces an adrenomedullin (AM) receptor, designated AM₁^[4]
• with RAMP3: produces a dual CGRP/AM receptor designated AM₂

These receptors are linked to the G protein G_s,^[5] 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).^[6]

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.^[7]

Structure

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.^[8]

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.^[9] 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.^[10]

Adrenomedullin receptor

Expression

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

Clinical significance

Calcitonin gene-related peptide receptor antagonists are approved for the treatment of migraine.

References

Further reading

• Born W, Muff R, Fischer JA . 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 . 2002 . 11921352 . 10.1002/jemt.10051 . 20459079 .
• Yallampalli C, Chauhan M, Thota CS . Calcitonin gene-related peptide in pregnancy and its emerging receptor heterogeneity. . Trends Endocrinol. Metab. . 13 . 6 . 263–9 . 2003 . 12128288 . 10.1016/s1043-2760(02)00563-5. 28476322 . etal.
• Foord SM, Craig RK . Isolation and characterisation of a human calcitonin-gene-related-peptide receptor. . Eur. J. Biochem. . 170 . 1–2 . 373–9 . 1988 . 2826160 . 10.1111/j.1432-1033.1987.tb13710.x . free .
• Skofitsch G, Jacobowitz DM . Autoradiographic distribution of 125I calcitonin gene-related peptide binding sites in the rat central nervous system. . Peptides . 6 . 5 . 975–86 . 1986 . 3001670 . 10.1016/0196-9781(85)90331-6 . 19435035 .
• Flühmann B, Muff R, Hunziker W . A human orphan calcitonin receptor-like structure. . Biochem. Biophys. Res. Commun. . 206 . 1 . 341–7 . 1995 . 7818539 . 10.1006/bbrc.1995.1047 . etal.
• Aiyar N, Rand K, Elshourbagy NA . A cDNA encoding the calcitonin gene-related peptide type 1 receptor. . J. Biol. Chem. . 271 . 19 . 11325–9 . 1996 . 8626685 . 10.1074/jbc.271.19.11325 . etal. free .
• McLatchie LM, Fraser NJ, Main MJ . RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. . Nature . 393 . 6683 . 333–9 . 1998 . 9620797 . 10.1038/30666 . 1998Natur.393..333M . 4364526 . etal.
• Sams A, Jansen-Olesen I . Expression of calcitonin receptor-like receptor and receptor-activity-modifying proteins in human cranial arteries. . Neurosci. Lett. . 258 . 1 . 41–4 . 1999 . 9876047 . 10.1016/S0304-3940(98)00844-1 . 371196 .
• Kamitani S, Asakawa M, Shimekake Y . The RAMP2/CRLR complex is a functional adrenomedullin receptor in human endothelial and vascular smooth muscle cells. . FEBS Lett. . 448 . 1 . 111–4 . 1999 . 10217420 . 10.1016/S0014-5793(99)00358-0 . 23729715 . etal. free . 1999FEBSL.448..111K .
• Aldecoa A, Gujer R, Fischer JA, Born W . 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 . 2000 . 10767413 . 10.1016/S0014-5793(00)01387-9 . 32098863 . free . 2000FEBSL.471..156A .
• Frayon S, Cueille C, Gnidéhou S . Dexamethasone increases RAMP1 and CRLR mRNA expressions in human vascular smooth muscle cells. . Biochem. Biophys. Res. Commun. . 270 . 3 . 1063–7 . 2000 . 10772950 . 10.1006/bbrc.2000.2552 . etal.
• Kuwasako K, Shimekake Y, Masuda M . Visualization of the calcitonin receptor-like receptor and its receptor activity-modifying proteins during internalization and recycling. . J. Biol. Chem. . 275 . 38 . 29602–9 . 2000 . 10882736 . 10.1074/jbc.M004534200 . etal. free .
• Evans BN, Rosenblatt MI, Mnayer LO . CGRP-RCP, a novel protein required for signal transduction at calcitonin gene-related peptide and adrenomedullin receptors. . J. Biol. Chem. . 275 . 40 . 31438–43 . 2000 . 10903324 . 10.1074/jbc.M005604200 . etal. free .
• Hilairet S, Foord SM, Marshall FH, Bouvier M . 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 . 2001 . 11387328 . 10.1074/jbc.M102722200 . free .
• Kamitani S, Sakata T . Glycosylation of human CRLR at Asn123 is required for ligand binding and signaling. . Biochim. Biophys. Acta . 1539 . 1–2 . 131–9 . 2001 . 11389975 . 10.1016/S0167-4889(01)00100-8 . free .
• Nikitenko LL, Brown NS, Smith DM . 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 . 2001 . 11420389 . 10.1093/molehr/7.7.655 . etal. free .
• Hilairet S, Bélanger C, Bertrand J . 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 . 2001 . 11535606 . 10.1074/jbc.M107323200 . etal. free .
• Aiyar N, Disa J, Pullen M, Nambi P . 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 . 2002 . 11693189 . 10.1023/A:1011907328682 . 26037173 .
• Hagner S, Haberberger RV, Overkamp D . Expression and distribution of calcitonin receptor-like receptor in human hairy skin. . Peptides . 23 . 1 . 109–16 . 2002 . 11814625 . 10.1016/S0196-9781(01)00586-1 . 6936664 . etal.
• Hill H, Pioszak A . Bacterial expression and purification of a heterodimeric adrenomedullin receptor extracellular domain complex using DsbC-assisted disulfide shuffling. . Protein Expr. Purif.. 88 . 1 . 107–13 . 2013 . 23247088 . 10.1016/j.pep.2012.11.019 . 3568255.

External links

• Web site: Calcitonin receptors: CALCRL . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology .

Notes and References

1. Aiyar N, Rand K, Elshourbagy NA, Zeng Z, Adamou JE, Bergsma DJ, Li Y . A cDNA encoding the calcitonin gene-related peptide type 1 receptor . J. Biol. Chem. . 271 . 19 . 11325–9 . May 1996 . 8626685 . 10.1074/jbc.271.19.11325 . free .
2. McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, Solari R, Lee MG, Foord SM . RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor . Nature . 393 . 6683 . 333–9 . May 1998 . 9620797 . 10.1038/30666 . 1998Natur.393..333M . 4364526 .
3. Foord SM, Marshall FH . RAMPs: accessory proteins for seven transmembrane domain receptors . Trends Pharmacol. Sci. . 20 . 5 . 184–7 . May 1999 . 10354609 . 10.1016/S0165-6147(99)01347-4 .
4. Kamitani S, Asakawa M, Shimekake Y, Kuwasako K, Nakahara K, Sakata T . The RAMP2/CRLR complex is a functional adrenomedullin receptor in human endothelial and vascular smooth muscle cells . FEBS Lett. . 448 . 1 . 111–4 . April 1999 . 10217420 . 10.1016/S0014-5793(99)00358-0 . 23729715 . free . 1999FEBSL.448..111K .
5. Web site: Receptor properties . SenseLab Project: Membrane properties resource . Yale University . https://web.archive.org/web/20090228070451/http://senselab.med.yale.edu/NeuronDB/receptors2.asp#Calcitonin,%20amylin,%20CGRP%20and%20adrenomedullin%20receptors, . 2009-02-28 . 2008-09-28 . dead .
6. Arulmani, U. . Eur J Pharmacol . 500 . 1–3. 315–30 . 2004 . 15464043 . 10.1016/j.ejphar.2004.07.035. Calcitonin gene-related peptide and its role in migraine pathophysiology. etal.
7. Web site: How the germ behind flesh-eating disease hijacks neurons to avoid immune destruction.

8. ter Haar E, Koth CM, Abdul-Manan N, Swenson L, Coll JT, Lippke JA, Lepre CA, Garcia-Guzman M, Moore JM . 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 . September 2010 . 20826335 . 10.1016/j.str.2010.05.014 . free .

9. Weston C, Winfield I, Harris M, Hodgson R, Shah A, Dowell SJ, Mobarec JC, Woodlock DA, Reynolds CA, Poyner DR, Watkins HA, Ladds G . 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 . October 2016 . 27566546 . 5063977 . 10.1074/jbc.M116.751362 . free .
10. Woolley MJ, Reynolds CA, Simms J, Walker CS, Mobarec JC, Garelja ML, Conner AC, Poyner DR, Hay DL . 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 . July 2017 . 28705698 . 5609567. 10.1016/j.bcp.2017.07.005 .