CALCRL

CALCRL
3N7S.pdb.png
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCALCRL, CGRPR, CRLR, calcitonin receptor like receptor
External IDsOMIM: 114190 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
Band2q32.1Start187,341,964 bp[1]
End187,448,460 bp[1]
RNA expression pattern
PBB GE CALCRL 206331 at fs.png

PBB GE CALCRL 210815 s at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
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 MbChr 2: 84.33 – 84.43 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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]

Function[edit]

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]

Wounds[edit]

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 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.[11]

Structure[edit]

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]

Expression[edit]

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

Clinical significance[edit]

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

References[edit]

  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. Archived from the original on 2009-02-28. 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. ^ https://medicalxpress.com/news/2018-05-germ-flesh-eating-disease-hijacks-neurons.html
  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 5063977. 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 5609567. PMID 28705698.
  15. ^ 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]

External links[edit]