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CGRP receptor

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Target not currently curated in GtoImmuPdb

Target id: 48

Nomenclature: CGRP receptor

Family: Calcitonin receptors

Contents:

Quaternary Structure: Subunits
RAMP1 (Accessory protein)
calcitonin receptor-like receptor
Previous and Unofficial Names Click here for help
CGRP1
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  CGRP receptor ectodomain in complex with RAMP1
PDB Id:  3N7P
Resolution:  2.8Å
Species:  Human
References:  53
Image of receptor 3D structure from RCSB PDB
Description:  CGRP receptor ectodomain in complex with antagonist
PDB Id:  3N7S
Ligand:  olcegepant
Resolution:  2.1Å
Species:  Human
References:  53
Image of receptor 3D structure from RCSB PDB
Description:  CGRP receptor ectodomain in complex with antagonist, ligand MK-0974
PDB Id:  3N7R
Ligand:  telcagepant
Resolution:  2.9Å
Species:  Human
References:  53
Image of receptor 3D structure from RCSB PDB
Description:  CGRP receptor ectodomain in complex with CGRP27–37 [Asp31, Pro34, Phe35]
PDB Id:  4RWG
Resolution:  2.44Å
Species:  Human
References:  9
Natural/Endogenous Ligands Click here for help
adrenomedullin {Sp: Human} , adrenomedullin {Sp: Mouse} , adrenomedullin {Sp: Rat}
adrenomedullin 2/intermedin {Sp: Human} , adrenomedullin 2/intermedin {Sp: Mouse} , adrenomedullin 2/intermedin {Sp: Rat}
α-CGRP {Sp: Human}
β-CGRP {Sp: Human} , β-CGRP {Sp: Mouse}
α-CGRP {Sp: Mouse, Rat}
β-CGRP {Sp: Rat}
α-CGRP-(8-37) (rat)
Comments: α-CGRP and β-CGRP are the principal endogenous agonists
Potency order of endogenous ligands (Human)
α-CGRP (CALCA, P06881), β-CGRP (CALCB, P10092) > adrenomedullin (ADM, P35318) ≥ adrenomedullin 2/intermedin (ADM2, Q7Z4H4) > amylin (IAPP, P10997)

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Agonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[Cys(Et)2,7]α-CGRP (human) Peptide Click here for species-specific activity table Hs Full agonist 10.5 pKi 44
⤷ pKi 10.5 [44]
β-CGRP {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 9.9 – 11.0 pKi 1,37
⤷ pKi 9.9 – 11.0 [1,37]
α-CGRP {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 9.7 – 10.0 pKi 1,37
⤷ pKi 9.7 – 10.0 [1,37]
adrenomedullin {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Immunopharmacology Ligand Hs Full agonist 8.1 pKi 1,37
⤷ pKi 8.1 [1,37]
[Cys(ACM)2,7]CGRP Peptide Hs Partial agonist 8.0 pKi 1
⤷ pKi 8.0 [1]
adrenomedullin 2/intermedin {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 7.5 – 9.1 pEC50 27
⤷ pEC50 7.5 – 9.1 [27]
β-CGRP {Sp: Rat} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Rn Full agonist 8.2 – 9.3 pIC50 3,12,29,45
⤷ pIC50 8.2 – 9.3 [3,12,29,45]
α-CGRP {Sp: Mouse, Rat} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Rn Full agonist 8.2 – 8.9 pIC50 3,12,29,45
⤷ pIC50 8.2 – 8.9 [3,12,29,45]
α-CGRP {Sp: Mouse, Rat} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Mm Full agonist 8.2 pIC50 28
⤷ pIC50 8.2 [28]
adrenomedullin {Sp: Rat} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Rn Full agonist 6.8 – 8.8 pIC50 29,45
⤷ pIC50 6.8 – 8.8 [29,45]
adrenomedullin {Sp: Rat} Peptide Click here for species-specific activity table Mm Full agonist 7.6 pIC50 28
⤷ pIC50 7.6 [28]
[125I]αCGRP (mouse, rat) Peptide Ligand is labelled Ligand is radioactive Hs Full agonist - -
⤷
View species-specific agonist tables
Agonist Comments
Reference [29] uses the rat calcitonin receptor-like receptor but mouse RAMP1.
Reference [12] uses the rat calcitonin receptor-like receptor but human RAMP1.

[Cys(ACM)2,7]-CGRP and [Cys(Et)2,7]-CGRP were introduced as selective CGRP2 agonists. This receptor phenotype is now considered to be a mixture of AM and AMY receptors [21]. [Cys(ACM)2,7]-CGRP is a partial agonist and the efficacy of [Cys(Et)2,7]-CGRP is very system dependent at CGRP and AMY receptors [6,22,44]. It is therefore recommended that these peptides are used with caution.
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
ubrogepant Small molecule or natural product Approved drug Hs Antagonist 10.8 pKB 41
⤷ pKB 10.8 [41]
zavegepant Small molecule or natural product Approved drug Hs Antagonist 10.7 pKB 14
⤷ pKB 10.7 (KB 2.2x10-11 M) [14]
Description: Antagonist activity at CGRP receptor in human SK-N-MC cell membranes , measured as inhibition of CGRP-stimulated cAMP production.
rimegepant Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 9.6 pKB 46
⤷ pKB 9.6 [46]
olcegepant Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 10.7 – 11.0 pKi 16,23,25,30,35
⤷ pKi 10.7 – 11.0 (Ki 2x10-11 – 1x10-11 M) [16,23,25,30,35]
atogepant Small molecule or natural product Approved drug Hs Antagonist 10.8 pKi 8
⤷ pKi 10.8 (Ki 1.5x10-11 M) [8]
Description: In a recombinant receptor binding assay, antagonising 125I-CGRP binding.
zavegepant Small molecule or natural product Approved drug Hs Antagonist 10.6 pKi 38
⤷ pKi 10.6 (Ki 2.3x10-11 M) [38]
compound 49 [PMID: 24405707] Small molecule or natural product Hs Antagonist 10.5 pKi 30
⤷ pKi 10.5 (Ki 3x10-11 M) [30]
Description: Binding assay with cell membranes treated with 125I-CGRP.
HTL22562 Small molecule or natural product Ligand has a PDB structure Hs Antagonist 10.5 pKi 10
⤷ pKi 10.5 [10]
Description: Human CGRP receptors (consisting of CLR and RAMP1) were expressed in insect Sf21 cells. Dissociation constant was determined in a radioligand binding assay using hCGRPR-containing membrane homegenates and 3H-telcagepant as tracer.
α-CGRP-(8-37) (human) Peptide Click here for species-specific activity table Hs Antagonist 9.2 – 9.6 pKi 1,37
⤷ pKi 9.2 – 9.6 [1,37]
telcagepant Small molecule or natural product Ligand has a PDB structure Hs Antagonist 9.1 pKi 50
⤷ pKi 9.1 [50]
compound 8 [Avgoustou et al., 2020] Small molecule or natural product Click here for species-specific activity table Hs Antagonist 9.1 pIC50 5
⤷ pIC50 9.1 [5]
Description: Inhibition of cAMP production.
α-CGRP-(8-37) (rat) Peptide Click here for species-specific activity table Rn Antagonist 8.2 – 8.9 pIC50 3,12,29,45
⤷ pIC50 8.2 – 8.9 [3,12,29,45]
View species-specific antagonist tables
Antagonist Comments
BIBN4096BS (and MK-0974) shows at least an order of magnitude selectivity for primate over non-primate receptors. The pharmacology of these compounds have recently been reviewed [42]. This affinity is conferred by a tryptophan at position 74 of human RAMP1 [35]. A variety of other non-peptide antagonists have been described, but their pharmacology has not been widely explored [35]. In functional assays the pA2 for CGRP 8-37 shows a wide spread of values from around 7 to nearly 9, depending on the system being analysed [19,24]. Thus it is difficult to use it to classify receptors.
Antibodies
Key to terms and symbols Click column headers to sort
Antibody Sp. Action Value Parameter Reference
erenumab Peptide Approved drug Primary target of this compound Hs Antagonist 10.7 pKi 51
⤷ pKi 10.7 (Ki 2x10-11 M) [51]
Description: Displacement binding of [(125)I]-CGRP at the human CGRP receptor
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gs family Adenylyl cyclase stimulation
References:  1,37
Secondary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family
Gq/G11 family 		Phospholipase C stimulation
Potassium channel
Comments:  CGRP can also activate a phosphatidylinositol 3-(OH) kinase dependent pathway and increase cGMP [47].
References:  2,34
Tissue Distribution Click here for help
Lung, non-pregnant and pregnant uterus, placenta.
Species:  Human
Technique:  Northern blotting.
References:  55
Spleen > liver, lung > spinal cord, whole brain > heart, kidney.
Note: CGRP receptor distribution can only be mapped reliably with [125I]-CGRP, as the calcitonin receptor-like receptor and the RAMPs form components of other receptors. Even radioligand binding is not without its problems as iodinated CGRP has appreciable affinity for amylin receptors.
Species:  Rat
Technique:  Radioligand binding.
References:  43
Functional Assays Click here for help
Measurement of cAMP in SK-N-MC cells endogenously expressing a CGRP receptor.
Species:  Human
Tissue:  SK-N-MC cells.
Response measured:  cAMP production.
References:  18
Measurement of blood vessel diameter.
Species:  Human
Tissue:  Isolated cranial arteries.
Response measured:  Smooth muscle relaxation.
References:  18
Measurement of cAMP levels in Drosophila Schneider 2 cells transfected with the rat calcitonin receptor-like receptor and RAMP1.
Species:  Rat
Tissue:  Drosophila Schneider 2 cells.
Response measured:  cAMP accumulation.
References:  3
Measurement of cAMP levels in COS-7 cells transfected with the mouse calcitonin receptor-like receptor and mouse RAMP1.
Species:  Mouse
Tissue:  COS-7 cells.
Response measured:  cAMP accumulation.
References:  28
Measurement of cAMP levels in COS-7 cells transfected with the human calcitonin receptor-like receptor and human RAMP1.
Species:  Human
Tissue:  COS-7 cells.
Response measured:  cAMP accumulation.
References:  6
Physiological Functions Click here for help
Antiproliferative effect.
Species:  Rat
Tissue:  Cultured vascular smooth muscle cells.
References:  32
Positive inotropic effects on the heart.
Species:  Human
Tissue:  Isolated myocardial trabeculae from the right atrium and left ventricle of the heart.
References:  49
Inhibition of food intake.
Species:  Rat
Tissue:  In vivo.
References:  52
Suppression of angiotensin-II-stimulated aldosterone production.
Species:  Rat
Tissue:  Zona glomerulosa cells of the adrenal gland.
References:  4
Inhibition of galanin-stimulated contraction.
Species:  Rat
Tissue:  Isolated non-pregnant uterus.
References:  55
Vasodilation.
Species:  Rat
Tissue:  Isolated perfused kidney.
References:  26
Inhibition of gastric emptying.
Species:  Rat
Tissue:  In vivo.
References:  36
Vasodilation.
Species:  Human
Tissue:  Isolated cerebral arteries.
References:  18
Positive inotropic and chronotropic effects on the heart.
Species:  Rat
Tissue:  Isolated ventricular cardiomyocytes.
References:  7
Vasodilation.
Species:  Human
Tissue:  Small arteries from thymus.
References:  13
Thermal hyperalgesia.
Species:  Mouse
Tissue:  Skin.
References:  40
Thermal hyperalgesia.
Species:  Mouse
Tissue:  Spinal cord.
References:  40
Vasodilation.
Species:  Rat
Tissue:  Mesenteric vascular bed and cerebral blood vessels.
References:  20,57
Mechanical nociception
Species:  Rat
Tissue:  Bone joints.
References:  11
Endothelium-independent vasodilation.
Species:  Human
Tissue:  Middle meningeal arteries.
References:  17
Physiological Consequences of Altering Gene Expression Click here for help
Protection against diet-induced obesity.
Species:  Mouse
Tissue: 
Technique:  CGRP knockout mouse
References:  56
Antisense oligonucleotides against RAMP1 increase pulmonary artery pressure.
Species:  Rat
Tissue: 
Technique:  Antisense oligonucleotide.
References:  48
In mice engineered for neural over-expression of human RAMP1, plasma extravasation in response to CGRP, a marker of neurogenic inflammation, was enhanced.
Species:  Mouse
Tissue: 
Technique:  Gene overexpression.
References:  59
Promotion of energy expenditure
Species:  Mouse
Tissue:  Central nervous system (RAMP1 overexpression)
Technique: 
References:  58
In a conditional RAMP1-/-mouse model, αCGRP-mediated reductions in blood pressure were lost and there were disturbances in pro-inflammatory cytokine production.
Species:  Mouse
Tissue: 
Technique:  Knockout.
References:  31,39,54
TRPV1 channel mobilisation and nociception.
Species:  Mouse
Tissue: 
Technique:  knockout
References:  15
Impaired wound healing in RAMP-/- mice is associated with reduced expression of VEFG-A, -B and –C.
Species:  Mouse
Tissue: 
Technique:  Knockout
References:  33

References

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