AM<sub>1</sub> receptor | Calcitonin receptors | IUPHAR/BPS Guide to PHARMACOLOGY

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AM1 receptor

Target not currently curated in GtoImmuPdb

Target id: 49

Nomenclature: AM1 receptor

Family: Calcitonin receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

Quaternary Structure: Subunits
RAMP2 (Accessory protein)
calcitonin receptor-like receptor
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Structure of the Extracellular Domain of Human RAMP2
PDB Id:  2XVT
Resolution:  2.05Å
Species:  Human
References:  24
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the human CRLR/RAMP2 extracellular complex
PDB Id:  3AQF
Resolution:  2.6Å
Species:  Human
References:  19
Image of receptor 3D structure from RCSB PDB
Description:  AM1 receptor ectodomain in complex with AM25-52
PDB Id:  4RWF
Resolution:  1.76Å
Species:  Human
References:  7
Natural/Endogenous Ligands
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}
Comments: Adrenomedullin and adrenomedullin 2/intermedin are the most likely physiological 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) > calcitonin (salmon)

Download all structure-activity data for this target as a CSV file

Agonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
α-CGRP {Sp: Human} Hs Full agonist 6.0 pKd 20
pKd 6.0 [20]
adrenomedullin {Sp: Human} Hs Full agonist 8.3 – 9.2 pKi 1,20
pKi 8.3 – 9.2 [1,20]
β-CGRP {Sp: Human} Hs Full agonist 7.3 – 7.7 pKi 1,20
pKi 7.3 – 7.7 [1,20]
adrenomedullin 2/intermedin {Sp: Human} Hs Full agonist 7.5 – 8.3 pEC50 12
pEC50 7.5 – 8.3 [12]
adrenomedullin {Sp: Rat} Rn Full agonist 8.7 – 9.3 pIC50 2,8,14,22
pIC50 8.7 – 9.3 [2,8,14,22]
AM-(11-50) (rat) Rn Full agonist 8.4 pIC50 22
pIC50 8.4 [22]
adrenomedullin {Sp: Rat} Mm Full agonist 8.0 pIC50 13
pIC50 8.0 [13]
β-CGRP {Sp: Rat} Rn Full agonist 6.7 – 6.8 pIC50 2,8,14
pIC50 6.7 – 6.8 [2,8,14]
α-CGRP {Sp: Mouse, Rat} Rn Full agonist 6.6 pIC50 2
pIC50 6.6 [2]
View species-specific agonist tables
Agonist Comments
Reference [14] uses the rat calcitonin receptor-like receptor but mouse RAMP2.
Reference [8] uses the rat calcitonin receptor-like receptor but human RAMP2.

There is evidence that the actions of AM2/intermedin are likely to be system-dependent; there is one report that it is a partial agonist on AM1 receptors [28].
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) Hs Antagonist 7.0 – 7.8 pKi 11
pKi 7.0 – 7.8 (Ki 1x10-7 – 1.58x10-8 M) [11]
α-CGRP-(8-37) (human) Hs Antagonist 5.0 – 7.0 pKi 1,20
pKi 5.0 – 7.0 [1,20]
AM-(20-50) (rat) Rn Antagonist 7.0 – 8.5 pIC50 2,8,14,22
pIC50 7.0 – 8.5 [2,8,14,22]
AM-(20-50) (rat) Mm Antagonist 7.5 pIC50 13
pIC50 7.5 [13]
α-CGRP-(8-37) (rat) Rn Antagonist 7.0 – 7.1 pIC50 2,8,14
pIC50 7.0 – 7.1 [2,8,14]
View species-specific antagonist tables
Antagonist Comments
High concentrations of AM22-52 will also block CGRP receptors [6]. No antagonist satisfactorily discriminates between human AM1 and AM2 receptors, although in rats AM22-52 shows a tendency to preferentially block AM1 receptors. Even here the difference is small [11].
Primary Transduction Mechanisms
Transducer Effector/Response
Gs family Adenylate cyclase stimulation
References:  1,20
Secondary Transduction Mechanisms
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 [21].
References:  3,15
Tissue Distribution
Lung, non-pregnant and pregnant uterus, placenta.
Species:  Human
Technique:  Northern blotting.
References:  27
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 CLR 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:  23
Functional Assays
Measurement of cAMP in COS-7 cells transfected with the human calcitonin receptor-like receptor and RAMP2.
Species:  Human
Tissue:  COS-7 cells.
Response measured:  cAMP production.
References:  11
Measurement of cAMP levels in COS-7 cells transfected with the rat calcitonin receptor-like receptor and mouse RAMP2.
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 RAMP2.
Species:  Mouse
Tissue:  COS-7 cells.
Response measured:  cAMP accumulation.
References:  13
Measurement of cAMP levels in COS-7 cells transfected with the rat calcitonin receptor-like receptor and human RAMP2.
Species:  Rat
Tissue:  COS-7 cells.
Response measured:  cAMP accumulation.
References:  8
Measurement of cAMP levels in Drosophila Schneider 2 cells transfected with the rat calcitonin receptor-like receptor and RAMP2.
Species:  Rat
Tissue:  Drosophila Schneider 2 cells
Response measured:  cAMP accumulation.
References:  2
Physiological Functions
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:  4
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:  Rat
Tissue:  Adrenal slices and dispersed adrenocortical cells.
References:  5
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:  27
Adrenomedullin is a potent hypotensive peptide.
Species:  Rat
Tissue:  In vivo
References:  18
Physiological Consequences of Altering Gene Expression
Deletion of the RAMP2 gene leads to impaired vascular (blood and lymphatic) development and embryonic lethality. Although RAMP2 may also be a component of other receptors, the similarity in phenotype of RAMP2-/- to AM-/- mice suggests that RAMP2-based receptors are physiological mediators of AM signalling during development.
Species:  Mouse
Tissue: 
Technique:  Knockout.
References:  10,16
Overexpression of RAMP2 in smooth muscle enhances the hypotensive effect of AM and increases relaxation of the aorta in response to AM.
Species:  Mouse
Tissue: 
Technique:  Gene overexpression.
References:  25
Deletion of the gene for calcitonin receptor-like receptor leads to severe oedema and embryonic lethality. Although the calcitonin receptor-like receptor is a component of other receptors, the similarity in phenotype of RAMP2-/-, AM-/- and Calcrl-/- mice suggests that AM1 receptor complexes are the physiological mediators of AM signalling during development.
Species:  Mouse
Tissue: 
Technique:  Knockout.
References:  9
Maintenance of cerebral blood flow.
Species:  Mouse
Tissue:  Cerebral blood vessels
Technique:  knockout
References:  17
Protection of renal tubular cells from chemical injury.
Species:  Mouse
Tissue:  Kidney
Technique:  knockout
References:  26
Regulation of cardiac metabolism and maintenance of mitochondrial structure. This study used a RAMP2 knockout model and so it should be noted that RAMP2 can interact with other proteins besides CLR.
Species:  Mouse
Tissue:  Heart
Technique:  knockout
References:  29

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. Aldecoa A, Gujer R, Fischer JA, Born W. (2000) Mammalian calcitonin receptor-like receptor/receptor activity modifying protein complexes define calcitonin gene-related peptide and adrenomedullin receptors in Drosophila Schneider 2 cells. FEBS Lett., 471 (2-3): 156-60. [PMID:10767413]

3. 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]

4. 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]

5. 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]

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

7. Booe JM, Walker CS, Barwell J, Kuteyi G, Simms J, Jamaluddin MA, Warner ML, Bill RM, Harris PW, Brimble MA et al.. (2015) Structural Basis for Receptor Activity-Modifying Protein-Dependent Selective Peptide Recognition by a G Protein-Coupled Receptor. Mol. Cell, 58 (6): 1040-52. [PMID:25982113]

8. Bühlmann N, Leuthäuser K, Muff R, Fischer JA, Born W. (1999) A receptor activity modifying protein (RAMP)2-dependent adrenomedullin receptor is a calcitonin gene-related peptide receptor when coexpressed with human RAMP1. Endocrinology, 140 (6): 2883-90. [PMID:10342881]

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. Fritz-Six KL, Dunworth WP, Li M, Caron KM. (2008) Adrenomedullin signaling is necessary for murine lymphatic vascular development. J. Clin. Invest., 118 (1): 40-50. [PMID:18097475]

11. 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]

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

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. Ichikawa-Shindo Y, Sakurai T, Kamiyoshi A, Kawate H, Iinuma N, Yoshizawa T, Koyama T, Fukuchi J, Iimuro S, Moriyama N et al.. (2008) The GPCR modulator protein RAMP2 is essential for angiogenesis and vascular integrity. J. Clin. Invest., 118 (1): 29-39. [PMID:18097473]

17. Igarashi K, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Yamauchi A, Toriyama Y, Tanaka M, Liu T, Xian X et al.. (2014) Pathophysiological roles of adrenomedullin-RAMP2 system in acute and chronic cerebral ischemia. Peptides, 62: 21-31. [PMID:25252154]

18. 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]

19. Kusano S, Kukimoto-Niino M, Hino N, Ohsawa N, Okuda K, Sakamoto K, Shirouzu M, Shindo T, Yokoyama S. (2012) Structural basis for extracellular interactions between calcitonin receptor-like receptor and receptor activity-modifying protein 2 for adrenomedullin-specific binding. Protein Sci., 21 (2): 199-210. [PMID:22102369]

20. McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, Solari R, Lee MG, Foord SM. (1998) RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature, 393 (6683): 333-9. [PMID:9620797]

21. 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]

22. Oliver KR, Kane SA, Salvatore CA, Mallee JJ, Kinsey AM, Koblan KS, Keyvan-Fouladi N, Heavens RP, Wainwright A, Jacobson M et al.. (2001) Cloning, characterization and central nervous system distribution of receptor activity modifying proteins in the rat. Eur. J. Neurosci., 14 (4): 618-28. [PMID:11556887]

23. 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]

24. Quigley A, Pike ACW, Burgess-Brown N, Krojer T, Shrestha L, Goubin S, Kim J, Das S, Muniz JRC, Canning P, Chaikuad A, Vollmar M, Von Delft F, Arrowsmith CH, Weigelt J, Edwards AM, Bountra C, Barr AJ, Carpenter EP. Structure of the Extracellular Domain of Human Ramp2. Accessed on 20/07/2012. Modified on 20/07/2012. PDB, http://www.rcsb.org/pdb/explore/explore.do?pdbId=2XVT

25. Tam CW, Husmann K, Clark NC, Clark JE, Lazar Z, Ittner LM, Götz J, Douglas G, Grant AD, Sugden D et al.. (2006) Enhanced vascular responses to adrenomedullin in mice overexpressing receptor-activity-modifying protein 2. Circ. Res., 98 (2): 262-70. [PMID:16373602]

26. Uetake R, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Iesato Y, Yoshizawa T, Koyama T, Yang L, Toriyama Y et al.. (2014) Adrenomedullin-RAMP2 system suppresses ER stress-induced tubule cell death and is involved in kidney protection. PLoS ONE, 9 (2): e87667. [PMID:24505304]

27. 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]

28. Wunder F, Rebmann A, Geerts A, Kalthof B. (2008) Pharmacological and kinetic characterization of adrenomedullin 1 and calcitonin gene-related peptide 1 receptor reporter cell lines. Mol. Pharmacol., 73 (4): 1235-43. [PMID:18174292]

29. Yoshizawa T, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Iesato Y, Koyama T, Uetake R, Yang L, Yamauchi A et al.. (2013) Novel regulation of cardiac metabolism and homeostasis by the adrenomedullin-receptor activity-modifying protein 2 system. Hypertension, 61 (2): 341-51. [PMID:23297372]

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