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]
The calcitonin receptor-like (CALCRL) protein is a class BG protein-coupled receptor (GPCR) characterized by seven transmembrane helices and a relatively largeN-terminal extracellular domain (ECD) comprising 100–160 residues and three conserveddisulfide bonds. CALCRL forms functional heterodimeric complexes with one of three single transmembranereceptor activity-modifying proteins (RAMPs), namely RAMP1, RAMP2, or RAMP3, which determine its ligand specificity. The extracellular domain of CALCRL consists of oneα-helix, two antiparallelβ-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]
The CGRP family of receptors including CALCRL can couple to G-proteinGαs,Gαi andGαq 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]
CALCRL bindsRamp2 to form the adrenomedullin receptor 1 (AM1), while it bindsRamp3 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 ofadrenomedullin causes vasodilation and decreased blood pressure via binding to its receptors.[17]
In wounds, CGRP receptors found innerve 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 orbotox have been demonstrated toblock CGRP cascade, thereby allowing immune system involvement and control of pathogens, resulting in complete control and recovery.[18]
^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.PMID9620797.S2CID4364526.
^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.PMID10354609.
^"Receptor properties".SenseLab Project: Membrane properties resource. Yale University. Archived fromthe original on 2009-02-28. Retrieved2008-09-28.
^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.PMID15464043.
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.PMID11921352.S2CID20459079.
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.PMID12128288.S2CID28476322.
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.PMID3001670.S2CID19435035.
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.PMID7818539.
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.PMID9620797.S2CID4364526.
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.PMID9876047.S2CID371196.
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.PMID10772950.
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.PMID11693189.S2CID26037173.
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.PMID11814625.S2CID6936664.
