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AM2 receptor

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Target not currently curated in GtoImmuPdb

Target id: 50

Nomenclature: AM2 receptor

Family: Calcitonin receptors

Contents:

Quaternary Structure: Subunits
RAMP3 (Accessory protein)
calcitonin receptor-like receptor
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: Adrenomedullin and adrenomedullin 2/intermedin are the most potent endogenous agonists
Potency order of endogenous ligands (Human)
adrenomedullin (ADM, P35318) ≥ adrenomedullin 2/intermedin (ADM2, Q7Z4H4) ≥ α-CGRP (CALCA, P06881), β-CGRP (CALCB, P10092) > amylin (IAPP, P10997)

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Agonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
adrenomedullin {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Immunopharmacology Ligand Hs Full agonist 8.3 – 9.0 pKi 1,10
⤷ pKi 8.3 – 9.0 [1,10]
α-CGRP {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 6.5 – 6.8 pKi 1,10
⤷ pKi 6.5 – 6.8 [1,10]
adrenomedullin 2/intermedin {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 8.9 – 10.1 pEC50 11
⤷ pEC50 8.9 – 10.1 [11]
adrenomedullin {Sp: Rat} Peptide Click here for species-specific activity table Mm Full agonist 8.2 pIC50 13
⤷ pIC50 8.2 [13]
adrenomedullin {Sp: Rat} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Rn Full agonist 8.2 pIC50 14
⤷ pIC50 8.2 [14]
α-CGRP {Sp: Mouse, Rat} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Rn Full agonist 7.7 pIC50 14
⤷ pIC50 7.7 [14]
β-CGRP {Sp: Rat} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Rn Full agonist 7.7 pIC50 14
⤷ pIC50 7.7 [14]
α-CGRP {Sp: Mouse, Rat} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Mm Full agonist 7.3 – 7.6 pIC50 13
⤷ pIC50 7.3 – 7.6 [13]
β-CGRP {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 7.0 – 7.5 pIC50 1,10
⤷ pIC50 7.0 – 7.5 [1,10]
View species-specific agonist tables
Agonist Comments
Reference [14] uses the rat calcitonin receptor-like receptor but mouse RAMP1.
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
AM-(22-52) (human) Peptide Click here for species-specific activity table Hs Antagonist 6.5 – 6.8 pKi 1,10
⤷ pKi 6.5 – 6.8 [1,10]
α-CGRP-(8-37) (human) Peptide Click here for species-specific activity table Hs Antagonist 6.5 pKi 1,10
⤷ pKi 6.5 [1,10]
compound 8 [Avgoustou et al., 2020] Small molecule or natural product Click here for species-specific activity table Hs Antagonist 9.2 pIC50 5
⤷ pIC50 9.2 [5]
Description: inhibition of cAMP production.
α-CGRP-(8-37) (rat) Peptide Click here for species-specific activity table Rn Antagonist 8.4 pIC50 14
⤷ pIC50 8.4 [14]
α-CGRP-(8-37) (rat) Peptide Mm Antagonist 8.2 pIC50 13
⤷ pIC50 8.2 [13]
AM-(20-50) (rat) Peptide Click here for species-specific activity table Rn Antagonist 7.8 pIC50 14
⤷ pIC50 7.8 [14]
AM-(20-50) (rat) Peptide Click here for species-specific activity table Mm Antagonist 7.3 – 7.4 pIC50 13
⤷ pIC50 7.3 – 7.4 [13]
AM-(22-52) (human) Peptide Click here for species-specific activity table Hs Antagonist - -
⤷
View species-specific antagonist tables
Antagonist Comments
High concentrations of AM (22-52) will also block CGRP receptors [6]. No antagonist satisfactorily discriminates between human AM1 and AM2 receptors, although in rats AM (22-52) shows a tendency to preferentially block AM1 receptors. Even here the difference is small [12].
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gs family Adenylyl cyclase stimulation
References:  1,10
Secondary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family
Gq/G11 family 		Guanylate cyclase stimulation
Phospholipase C stimulation
Other - See Comments
Comments:  AM can also activate phosphatidylinositol 3-(OH) kinase [2].
References:  15,17
Tissue Distribution Click here for help
Heart, spleen, lung > liver, spinal cord, skeletal muscle > brain, thyroid, stomach, kidney.
Note: AM receptor distribution can only be mapped reliably with [125I]-AM, as the calcitonin receptor-like receptor and the RAMPs form components of other receptors. It is not possible to distinguish between AM1 and AM2 receptors without full characterisation of the binding sites by appropriate inhibitors.
Species:  Rat
Technique:  Radioligand binding.
References:  18
Functional Assays Click here for help
Measurement of cAMP levels in COS-7 cells transfected with the rat calcitonin receptor-like receptor and mouse RAMP3.
Species:  Rat
Tissue:  COS-7 cells.
Response measured:  cAMP accumulation.
References:  14
Measurement of cAMP levels in COS-7 cells transfected with the mouse calcitonin receptor-like receptor and mouse RAMP3.
Species:  Mouse
Tissue:  COS-7 cells.
Response measured:  cAMP accumulation.
References:  13
Measurement of cAMP levels in COS-7 cells transfected with the human calcitonin receptor-like receptor and human RAMP3.
Species:  Human
Tissue:  COS-7 cells.
Response measured:  cAMP accumulation.
References:  12
Measurement of cAMP levels in COS-7 cells transfected with the rat calcitonin receptor-like receptor and human RAMP3.
Species:  Rat
Tissue:  COS-7 cells.
Response measured:  cAMP accumulation.
References:  12
Physiological Functions Click here for help
Increase in blood pressure upon adrenomedullin injection into the area postrema. It is not clear which AM receptor by which this function is mediated.
Species:  Rat
Tissue:  In vivo.
References:  3
At μM concentrations, adrenomedullin inhibits aldosterone production. At nM concentrations, adrenomedullin stimulates aldosterone secretion via a pathway involving adrenaline and noradrenaline. It is not clear by which AM receptor this function is mediated.
Species:  Human
Tissue:  Adrenal and dispersed adrenocortical cells.
References:  4
Inhibition of galanin-stimulated contraction. It is not clear by which AM receptor this function is mediated.
Species:  Rat
Tissue:  Isolated non-pregnant uterus.
References:  19
Adrenomedullin is a potent hypotensive peptide.
Species:  Rat
Tissue:  In vivo
References:  16
Physiological Consequences of Altering Gene Expression Click here for help
Deletion of the gene for calcitonin receptor-like receptor leads to severe oedema and embryonic lethality. The similarity in phenotype of RAMP2-/-, AM-/- and Calcrl-/- mice suggests that AM1 receptor complexes are the physiological mediators of AM signalling during development. Therefore AM2 receptors are likely to mediate other actions of AM.
Species:  Mouse
Tissue: 
Technique:  Knockout.
References:  9
A RAMP3 knockout mouse was viable with no obvious abnormalities apart from reduced weight in old age.
Species:  Mouse
Tissue: 
Technique:  Knockout mice
References:  8
Male mice, susceptible to hypertension, showed depressed cardiac function in a RAMP3 knockdown model. However, RAMP3 can act with other partners besides CLR.
Species:  Mouse
Tissue: 
Technique:  Knockdown model
References:  7
In a RAMP3 knockout model, mice showed reduced lymphatic drainage and reduced mobility of lymphatic endothelial cells. However, RAMP3 can act with other partners besides CLR.
Species:  Mouse
Tissue: 
Technique:  Knockdown model
References:  20
Regulation of lymphatic drainage. However, RAMP3 can act with other partners besides CLR.
Species:  Mouse
Tissue: 
Technique:  knockout
References:  20

References

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1. Aiyar N, Disa J, Pullen M, Nambi P. (2001) Receptor activity modifying proteins interaction with human and porcine calcitonin receptor-like receptor (CRLR) in HEK-293 cells. Mol Cell Biochem, 224 (1-2): 123-33. [PMID:11693189]

2. Ali N, Yousufzai SY, Abdel-Latif AA. (2000) Activation of particulate guanylate cyclase by adrenomedullin in cultured SV-40 transformed cat iris sphincter smooth muscle (SV-CISM-2) cells. Cell Signal, 12: 491-498. [PMID:10989285]

3. Allen MA, Ferguson AV. (1996) In vitro recordings from area postrema neurons demonstrate responsiveness to adrenomedullin. Am J Physiol, 270 (4 Pt 2): R920-5. [PMID:8967423]

4. Andreis PG, Neri G, Prayer-Galetti T, Rossi GP, Gottardo G, Malendowicz LK, Nussdorfer GG. (1997) Effects of adrenomedullin on the human adrenal glands: an in vitro study. J Clin Endocrinol Metab, 82 (4): 1167-70. [PMID:9100590]

5. Avgoustou P. et al.. (2020) Discovery of a First-in-Class Potent Small Molecule Antagonist against the Adrenomedullin-2 Receptor. ACS Pharmacol Transl Sci, [Epub ahead of print]. DOI: 10.1021/acsptsci.0c00032

6. Bailey RJ, Hay DL. (2006) Pharmacology of the human CGRP1 receptor in Cos 7 cells. Peptides, 27 (6): 1367-75. [PMID:16375989]

7. Barrick CJ, Lenhart PM, Dackor RT, Nagle E, Caron KM. (2012) Loss of receptor activity-modifying protein 3 exacerbates cardiac hypertrophy and transition to heart failure in a sex-dependent manner. J Mol Cell Cardiol, 52 (1): 165-74. [PMID:22100352]

8. Dackor R, Fritz-Six K, Smithies O, Caron K. (2007) Receptor activity-modifying proteins 2 and 3 have distinct physiological functions from embryogenesis to old age. J Biol Chem, 282 (25): 18094-9. [PMID:17470425]

9. Dackor RT, Fritz-Six K, Dunworth WP, Gibbons CL, Smithies O, Caron KM. (2006) Hydrops fetalis, cardiovascular defects, and embryonic lethality in mice lacking the calcitonin receptor-like receptor gene. Mol Cell Biol, 26 (7): 2511-8. [PMID:16537897]

10. Fraser NJ, Wise A, Brown J, McLatchie LM, Main MJ, Foord SM. (1999) The amino terminus of receptor activity modifying proteins is a critical determinant of glycosylation state and ligand binding of calcitonin receptor-like receptor. Mol Pharmacol, 55: 1054-1059. [PMID:10347248]

11. Hay DL, Garelja ML, Poyner DR, Walker CS. (2018) Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25. Br J Pharmacol, 175 (1): 3-17. [PMID:29059473]

12. Hay DL, Howitt SG, Conner AC, Schindler M, Smith DM, Poyner DR. (2003) CL/RAMP2 and CL/RAMP3 produce pharmacologically distinct adrenomedullin receptors: a comparison of effects of adrenomedullin22-52, CGRP8-37 and BIBN4096BS. Br J Pharmacol, 140 (3): 477-86. [PMID:12970090]

13. Husmann K, Born W, Fischer JA, Muff R. (2003) Three receptor-activity-modifying proteins define calcitonin gene-related peptide or adrenomedullin selectivity of the mouse calcitonin-like receptor in COS-7 cells. Biochem Pharmacol, 66 (11): 2107-15. [PMID:14609735]

14. Husmann K, Sexton PM, Fischer JA, Born W. (2000) Mouse receptor-activity-modifying proteins 1, -2 and -3: amino acid sequence, expression and function. Mol Cell Endocrinol, 162 (1-2): 35-43. [PMID:10854696]

15. Ichikawa I, Brenner BM. (1976) Of unglazed pottery and glomerular sieving. Kidney Int, 10 (3): 264-7. [PMID:787620]

16. Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, Eto T. (1993) Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun, 192 (2): 553-60. [PMID:8387282]

17. Nishimatsu H, Suzuki E, Nagata D, Moriyama N, Satonaka H, Walsh K, Sata M, Kangawa K, Matsuo H, Goto A et al.. (2001) Adrenomedullin induces endothelium-dependent vasorelaxation via the phosphatidylinositol 3-kinase/Akt-dependent pathway in rat aorta. Circ Res, 89 (1): 63-70. [PMID:11440979]

18. Owji AA, Smith DM, Coppock HA, Morgan DG, Bhogal R, Ghatei MA, Bloom SR. (1995) An abundant and specific binding site for the novel vasodilator adrenomedullin in the rat. Endocrinology, 136 (5): 2127-34. [PMID:7720662]

19. Upton PD, Austin C, Taylor GM, Nandha KA, Clark AJ, Ghatei MA, Bloom SR, Smith DM. (1997) Expression of adrenomedullin (ADM) and its binding sites in the rat uterus: increased number of binding sites and ADM messenger ribonucleic acid in 20-day pregnant rats compared with nonpregnant rats. Endocrinology, 138 (6): 2508-14. [PMID:9165042]

20. Yamauchi A, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Igarashi K, Toriyama Y, Tanaka M, Liu T, Xian X et al.. (2014) Functional differentiation of RAMP2 and RAMP3 in their regulation of the vascular system. J Mol Cell Cardiol, 77: 73-85. [PMID:25264174]

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