Biology:CALCRL

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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]

Tissue distribution

RNA expression charts show highest expression in lung and adipose tissue in humans.[2] 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.[3]

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.[4][5]

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:[6][7]

  • with RAMP1: produces a CGRP receptor
  • with RAMP2: produces an adrenomedullin (AM) receptor, designated AM1[8]
  • with RAMP3: produces a dual CGRP/AM receptor designated AM2

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]

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.[11] 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.[12]

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.[13]

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.[14]

References

  1. ↑ "A cDNA encoding the calcitonin gene-related peptide type 1 receptor". The Journal of Biological Chemistry 271 (19): 11325–11329. May 1996. doi:10.1074/jbc.271.19.11325. PMID 8626685. 
  2. ↑ "Tissue expression of CALCRL - Summary - The Human Protein Atlas". https://www.proteinatlas.org/ENSG00000064989-CALCRL/tissue. 
  3. ↑ "Single cell type - CALCRL - The Human Protein Atlas". https://www.proteinatlas.org/ENSG00000064989-CALCRL/single+cell. 
  4. ↑ "Calcitonin and calcitonin receptor-like receptors: common themes with family B GPCRs?". British Journal of Pharmacology 166 (1): 51–65. May 2012. doi:10.1111/j.1476-5381.2011.01525.x. PMID 21649645. 
  5. ↑ PDB: 3N7S​; "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. September 2010. doi:10.1016/j.str.2010.05.014. PMID 20826335. 
  6. ↑ "RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor". Nature 393 (6683): 333–339. May 1998. doi:10.1038/30666. PMID 9620797. Bibcode: 1998Natur.393..333M. 
  7. ↑ "RAMPs: accessory proteins for seven transmembrane domain receptors". Trends in Pharmacological Sciences 20 (5): 184–187. May 1999. doi:10.1016/S0165-6147(99)01347-4. PMID 10354609. 
  8. ↑ "The RAMP2/CRLR complex is a functional adrenomedullin receptor in human endothelial and vascular smooth muscle cells". FEBS Letters 448 (1): 111–114. April 1999. doi:10.1016/S0014-5793(99)00358-0. PMID 10217420. Bibcode: 1999FEBSL.448..111K. 
  9. ↑ "Receptor properties". SenseLab Project: Membrane properties resource. Yale University. http://senselab.med.yale.edu/NeuronDB/receptors2.asp#Calcitonin,%20amylin,%20CGRP%20and%20adrenomedullin%20receptors,. 
  10. ↑ "Calcitonin gene-related peptide and its role in migraine pathophysiology". European Journal of Pharmacology 500 (1–3): 315–330. October 2004. doi:10.1016/j.ejphar.2004.07.035. PMID 15464043. 
  11. ↑ "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. doi:10.1074/jbc.M116.751362. PMID 27566546. 
  12. ↑ "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. October 2017. doi:10.1016/j.bcp.2017.07.005. PMID 28705698. 
  13. ↑ "Adrenomedullin and Adrenomedullin-Targeted Therapy As Treatment Strategies Relevant for Sepsis". Frontiers in Immunology 9. 2018-02-19. doi:10.3389/fimmu.2018.00292. PMID 29520277. 
  14. ↑ "How the germ behind flesh-eating disease hijacks neurons to avoid immune destruction". https://medicalxpress.com/news/2018-05-germ-flesh-eating-disease-hijacks-neurons.html. 

Further reading



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