CALCRL

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]

CALCRL
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3AQF, 3N7P, 3N7R, 3N7S, 4RWF
Identifiers
Aliases	CALCRL, CGRPR, CRLR, calcitonin receptor like receptor, LMPHM8
External IDs	OMIM: 114190; MGI: 1926944; HomoloGene: 21179; GeneCards: CALCRL; OMA:CALCRL - orthologs
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2q32.1 Start 187,341,964 bp[1] End 187,448,460 bp[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band 2|2 D Start 84,160,970 bp[2] End 84,255,755 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right lung upper lobe of left lung Achilles tendon gallbladder lower lobe of lung right coronary artery left coronary artery smooth muscle tissue subcutaneous adipose tissue popliteal artery Top expressed in left lung lobe right lung right lung lobe vas deferens iris atrioventricular valve carotid body genital tubercle endothelial cell of lymphatic vessel semi-lunar valve More reference expression data BioGPS More reference expression data
Gene ontology Molecular function G protein-coupled receptor activity calcitonin receptor activity signal transducer activity protein binding transmembrane signaling receptor activity adrenomedullin receptor activity calcitonin gene-related peptide receptor activity adrenomedullin binding Cellular component integral component of membrane endosome membrane plasma membrane integral component of plasma membrane endoplasmic reticulum lysosome cytoplasm adrenomedullin receptor complex CGRP receptor complex Biological process negative regulation of smooth muscle contraction G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger receptor internalization cellular response to sucrose stimulus development of the heart cell surface receptor signaling pathway angiogenesis positive regulation of cell population proliferation protein transport negative regulation of inflammatory response calcium ion transport signal transduction positive regulation of smooth muscle cell proliferation G protein-coupled receptor signaling pathway adenylate cyclase-activating G protein-coupled receptor signaling pathway calcitonin gene-related peptide receptor signaling pathway adrenomedullin receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10203 54598 Ensembl ENSG00000064989 ENSMUSG00000059588 UniProt Q16602 Q9R1W5 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 Mb Chr 2: 84.16 – 84.26 Mb PubMed search [3] [4]
Wikidata
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Tissue distribution

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]

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.​^[8][9]

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:^[10][11]

• with RAMP1: produces a CGRP receptor
• with RAMP2: produces an adrenomedullin (AM) receptor, designated AM₁^[12]
• with RAMP3: produces a dual CGRP/AM receptor designated AM₂

These receptors are linked to the G protein G_s,^[13] 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).^[14]

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.^[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]

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.^[17]

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.^[18]