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AMY3 receptor

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Target not currently curated in GtoImmuPdb

Target id: 46

Nomenclature: AMY3 receptor

Family: Calcitonin receptors

Contents:

Quaternary Structure: Subunits
RAMP3 (Accessory protein)
CT receptor
Natural/Endogenous Ligands Click here for help
adrenomedullin {Sp: Human}
adrenomedullin 2/intermedin {Sp: Human}
amylin {Sp: Human} , amylin {Sp: Mouse, Rat}
calcitonin {Sp: Human} , calcitonin {Sp: Mouse, Rat}
α-CGRP {Sp: Human}
β-CGRP {Sp: Human} , β-CGRP {Sp: Mouse}
α-CGRP {Sp: Mouse, Rat}
β-CGRP {Sp: Rat}
Comments: Amylin is the principal endogenous agonist
Potency order of endogenous ligands (Human)
amylin (IAPP, P10997) > α-CGRP (CALCA, P06881), β-CGRP (CALCB, P10092) ≥ adrenomedullin 2/intermedin (ADM2, Q7Z4H4) ≥ calcitonin (CALCA, P01258) > adrenomedullin (ADM, P35318)

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Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
calcitonin (salmon) Peptide Approved drug Click here for species-specific activity table Rn Full agonist 8.2 pKi 3
⤷ pKi 8.2 [3]
amylin {Sp: Mouse, Rat} Peptide Click here for species-specific activity table Hs Full agonist 8.6 – 10.8 pEC50 1,4,7
⤷ pEC50 8.6 – 10.8 [1,4,7]
KBP-088 Peptide Click here for species-specific activity table Hs Agonist 9.4 pEC50 6
⤷ pEC50 9.4 (EC50 4x10-10 M) [6]
Description: β-arrestin recruitment assay.
calcitonin {Sp: Human} Peptide Approved drug Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 8.0 – 10.6 pEC50 1
⤷ pEC50 8.0 – 10.6 [1]
pramlintide Peptide Approved drug Click here for species-specific activity table Hs Agonist 9.1 – 9.3 pEC50 4
⤷ pEC50 9.1 – 9.3 (EC50 8.91x10-10 – 5.2x10-10 M) [4]
Description: Measuring ligand-induced cAMP production in COS and HEK293 cells.
davalintide Peptide Click here for species-specific activity table Hs Agonist 8.9 pEC50 6
⤷ pEC50 8.9 (EC50 1.3x10-9 M) [6]
Description: β-arrestin recruitment assay.
α-CGRP {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 7.6 – 9.7 pEC50 7,9-10
⤷ pEC50 7.6 – 9.7 [7,9-10]
β-CGRP {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 7.7 pEC50 7
⤷ pEC50 7.7 [7]
adrenomedullin {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Immunopharmacology Ligand Hs Full agonist 6.9 – 8.3 pEC50 7,10
⤷ pEC50 6.9 – 8.3 [7,10]
adrenomedullin 2/intermedin {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist ~7.0 pEC50 8
⤷ pEC50 ~7.0 [8]
calcitonin (salmon) Peptide Approved drug Click here for species-specific activity table Hs Full agonist - -
⤷
KBP-066 Peptide Click here for species-specific activity table Hs Agonist - - 12
⤷ [12]
Description: β-arrestin recruitment assay
View species-specific agonist tables
Agonist Comments
The AMY3 receptor is a heterodimeric complex of the calcitonin receptor and RAMP3 [11]. The variability in potency values reported is likely to reflect cell background such as the presence of other endogenous RAMPs and the calcitonin receptor-like receptor [13]. It is difficult to ascertain the contribution of such factors to the reported values.
Human amylin is rarely used because of its propensity to aggregate.
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
CT-(8-32) (salmon) Peptide Click here for species-specific activity table Hs Antagonist 7.9 pKB 7
⤷ pKB 7.9 [7]
AC187 Peptide Click here for species-specific activity table Hs Antagonist 7.7 pKB 7
⤷ pKB 7.7 [7]
α-CGRP-(8-37) (human) Peptide Click here for species-specific activity table Hs Antagonist 6.2 pKB 7
⤷ pKB 6.2 [7]
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gs family Adenylyl cyclase stimulation
References:  3,7,9-10,13
Tissue Distribution Click here for help
Lung > fundus (stomach) > spleen, brainstem, hypothalamus > liver, cortex, cerebellum.
Note: At present there is virtually no information on the co-localisation of CT with RAMP3. This data is based on the binding of [125I]-amylin and so is an aggregate for AMY1, AMY2 and AMY3 receptors.
Species:  Rat
Technique:  Radioligand binding.
References:  2
Functional Assays Click here for help
Measurement of cAMP levels in COS-7 cells transfected with AMY3 receptors (calcitonin receptor plus RAMP3).
Species:  Human
Tissue:  COS-7 cells.
Response measured:  cAMP accumulation.
References:  3,7,13
Physiological Functions Click here for help
Amylin inhibits glycolysis and increases free radical production and apoptosis. The receptor through which this happens is unclear.
Species:  Mouse
Tissue:  in vivo.
References:  14
Biologically Significant Variants Click here for help
Type:  Splice variants
Species:  Human
Description:  AMY3 receptors are formed by the interaction of RAMP3 with the CT receptor and its splice variants. The human CT(b) (formerly CTR1 or CTRI1+) receptor is of identical sequence to the human CT(a) receptor but contains a 16 amino acid insert in the first intracellular loop.
References:  5,13

References

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1. Armour SL, Foord S, Kenakin T, Chen WJ. (1999) Pharmacological characterization of receptor-activity-modifying proteins (RAMPs) and the human calcitonin receptor. J Pharmacol Toxicol Methods, 42 (4): 217-24. [PMID:11033437]

2. Bhogal R, Smith DM, Bloom SR. (1992) Investigation and characterization of binding sites for islet amyloid polypeptide in rat membranes. Endocrinology, 130 (2): 906-13. [PMID:1310282]

3. Christopoulos G, Perry KJ, Morfis M, Tilakaratne N, Gao Y, Fraser NJ, Main MJ, Foord SM, Sexton PM. (1999) Multiple amylin receptors arise from receptor activity-modifying protein interaction with the calcitonin receptor gene product. Mol Pharmacol, 56 (1): 235-42. [PMID:10385705]

4. Gingell JJ, Burns ER, Hay DL. (2014) Activity of pramlintide, rat and human amylin but not Aβ1-42 at human amylin receptors. Endocrinology, 155 (1): 21-6. [PMID:24169554]

5. Gorn AH, Rudolph SM, Flannery MR, Morton CC, Weremowicz S, Wang TZ, Krane SM, Goldring SR. (1995) Expression of two human skeletal calcitonin receptor isoforms cloned from a giant cell tumor of bone. The first intracellular domain modulates ligand binding and signal transduction. J Clin Invest, 95: 2680-2691. [PMID:7769107]

6. Gydesen S, Andreassen KV, Hjuler ST, Christensen JM, Karsdal MA, Henriksen K. (2016) KBP-088, a novel DACRA with prolonged receptor activation, is superior to davalintide in terms of efficacy on body weight. Am J Physiol Endocrinol Metab, 310 (10): E821-7. [PMID:26908506]

7. Hay DL, Christopoulos G, Christopoulos A, Poyner DR, Sexton PM. (2005) Pharmacological discrimination of calcitonin receptor: receptor activity-modifying protein complexes. Mol Pharmacol, 67 (5): 1655-65. [PMID:15692146]

8. Hong Y, Hay DL, Quirion R, Poyner DR. (2012) The pharmacology of adrenomedullin 2/intermedin. Br J Pharmacol, 166 (1): 110-20. [PMID:21658025]

9. Kuwasako K, Cao YN, Nagoshi Y, Tsuruda T, Kitamura K, Eto T. (2004) Characterization of the human calcitonin gene-related peptide receptor subtypes associated with receptor activity-modifying proteins. Mol Pharmacol, 65 (1): 207-13. [PMID:14722252]

10. Kuwasako K, Kitamura K, Nagoshi Y, Eto T. (2003) Novel calcitonin-(8-32)-sensitive adrenomedullin receptors derived from co-expression of calcitonin receptor with receptor activity-modifying proteins. Biochem Biophys Res Commun, 301 (2): 460-4. [PMID:12565884]

11. Poyner DR, Sexton PM, Marshall I, Smith DM, Quirion R, Born W, Muff R, Fischer JA, Foord SM. (2002) International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors. Pharmacol Rev, 54 (2): 233-46. [PMID:12037140]

12. Sonne N, Larsen AT, Andreassen KV, Karsdal MA, Henriksen K. (2020) The Dual Amylin and Calcitonin Receptor Agonist, KBP-066, Induces an Equally Potent Weight Loss Across a Broad Dose Range While Higher Doses May Further Improve Insulin Action. J Pharmacol Exp Ther, 373 (1): 92-102. [PMID:31992608]

13. Tilakaratne N, Christopoulos G, Zumpe ET, Foord SM, Sexton PM. (2000) Amylin receptor phenotypes derived from human calcitonin receptor/RAMP coexpression exhibit pharmacological differences dependent on receptor isoform and host cell environment. J Pharmacol Exp Ther, 294 (1): 61-72. [PMID:10871296]

14. Venkatanarayan A, Raulji P, Norton W, Chakravarti D, Coarfa C, Su X, Sandur SK, Ramirez MS, Lee J, Kingsley CV et al.. (2015) IAPP-driven metabolic reprogramming induces regression of p53-deficient tumours in vivo. Nature, 517 (7536): 626-30. [PMID:25409149]

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