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- Receptor guanylyl cyclase (RGC) family
- Transmembrane guanylyl cyclases
Transmembrane guanylyl cyclases C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
Transmembrane guanylyl cyclases are homodimeric receptors activated by a diverse range of endogenous ligands. GC-A, GC-B and GC-C are expressed predominantly in the cardiovascular system, skeletal system and intestinal epithelium, respectively. GC-D and GC-G are found in the olfactory neuropepithelium and Grüeneberg ganglion of rodents, respectively. GC-E and GC-F are expressed in retinal photoreceptors. Family members have conserved ligand-binding, catalytic (guanylyl cyclase) and regulatory domains with the exception of NPR-C which has an extracellular binding domain homologous to that of other NPRs, but with a truncated intracellular domain which appears to couple, via the Gi/o family of G proteins, to activation of phospholipase C, inwardly-rectifying potassium channels and inhibition of adenylyl cyclase activity [22].
Receptors
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GC-A (Guanylyl cyclase-A)
C
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GC-B (Guanylyl cyclase-B)
C
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GC-C (Guanylyl cyclase-C)
C
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NPR-C (natriuretic peptide receptor 3)
C
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GC-D (Guanylyl cyclase-D)
C
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GC-E (Guanylyl cyclase-E)
C
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GC-F (Guanylyl cyclase-F)
C
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GC-G (Guanylyl cyclase-G)
C
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References
1. Andresen H, Pérez-Ternero C, Robinson J, Dickey DM, Hobbs AJ, Potter LR, Levy FO, Cataliotti A, Moltzau LR. (2023) Novel enhancers of guanylyl cyclase-A activity acting via allosteric modulation. Br J Pharmacol, 180 (24): 3254-3270. [PMID:37522273]
2. Bach T, Bergholtz S, Riise J, Qvigstad E, Skomedal T, Osnes JB, Levy FO. (2014) Identification of small molecule NPR-B antagonists by high throughput screening--potential use in heart failure. Naunyn Schmiedebergs Arch Pharmacol, 387 (1): 5-14. [PMID:24297249]
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4. Chao YC, Chen CC, Lin YC, Breer H, Fleischer J, Yang RB. (2015) Receptor guanylyl cyclase-G is a novel thermosensory protein activated by cool temperatures. EMBO J, 34 (3): 294-306. [PMID:25452496]
5. Chao YC, Cheng CJ, Hsieh HT, Lin CC, Chen CC, Yang RB. (2010) Guanylate cyclase-G, expressed in the Grueneberg ganglion olfactory subsystem, is activated by bicarbonate. Biochem J, 432 (2): 267-73. [PMID:20738256]
6. Chen Y, Schaefer JJ, Iyer SR, Harders GE, Pan S, Sangaralingham SJ, Chen HH, Redfield MM, Burnett Jr JC. (2020) Long-term blood pressure lowering and cGMP-activating actions of the novel ANP analog MANP. Am J Physiol Regul Integr Comp Physiol, 318 (4): R669-R676. [PMID:32022596]
7. Delporte C, Poloczek P, Gossen D, Tastenoy M, Winand J, Christophe J. (1991) Characterization and regulation of atrial natriuretic peptide (ANP)-R1 receptors in the human neuroblastoma cell line NB-OK-1. Eur J Pharmacol, 207 (1): 81-8. [PMID:1680722]
8. Deschênes J, Duperé C, McNicoll N, L'Heureux N, Auger F, Fournier A, De Léan A. (2005) Development of a selective peptide antagonist for the human natriuretic peptide receptor-B. Peptides, 26 (3): 517-24. [PMID:15652659]
9. Edelson JD, Makhlina M, Silvester KR, Vengurlekar SS, Chen X, Zhang J, Koziol-White CJ, Cooper PR, Hallam TJ, Hay DW et al.. (2013) In vitro and in vivo pharmacological profile of PL-3994, a novel cyclic peptide (Hept-cyclo(Cys-His-Phe-d-Ala-Gly-Arg-d-Nle-Asp-Arg-Ile-Ser-Cys)-Tyr-[Arg mimetic]-NH(2)) natriuretic peptide receptor-A agonist that is resistant to neutral endopeptidase and acts as a bronchodilator. Pulm Pharmacol Ther, 26 (2): 229-38. [PMID:23154072]
10. Hamra FK, Eber SL, Chin DT, Currie MG, Forte LR. (1997) Regulation of intestinal uroguanylin/guanylin receptor-mediated responses by mucosal acidity. Proc Natl Acad Sci USA, 94 (6): 2705-10. [PMID:9122260]
11. Harris LA, Crowell MD. (2007) Linaclotide, a new direction in the treatment of irritable bowel syndrome and chronic constipation. Curr Opin Mol Ther, 9 (4): 403-10. [PMID:17694454]
12. Hobbs A, Foster P, Prescott C, Scotland R, Ahluwalia A. (2004) Natriuretic peptide receptor-C regulates coronary blood flow and prevents myocardial ischemia/reperfusion injury: novel cardioprotective role for endothelium-derived C-type natriuretic peptide. Circulation, 110 (10): 1231-5. [PMID:15337698]
13. Hu J, Zhong C, Ding C, Chi Q, Walz A, Mombaerts P, Matsunami H, Luo M. (2007) Detection of near-atmospheric concentrations of CO2 by an olfactory subsystem in the mouse. Science, 317 (5840): 953-7. [PMID:17702944]
14. Kambayashi Y, Nakajima S, Ueda M, Inouye K. (1989) A dicarba analog of beta-atrial natriuretic peptide (beta-ANP) inhibits guanosine 3',5'-cyclic monophosphate production induced by alpha-ANP in cultured rat vascular smooth muscle cells. FEBS Lett, 248 (1-2): 28-34. [PMID:2542088]
15. Lorget F, Kaci N, Peng J, Benoist-Lasselin C, Mugniery E, Oppeneer T, Wendt DJ, Bell SM, Bullens S, Bunting S et al.. (2012) Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. Am J Hum Genet, 91 (6): 1108-14. [PMID:23200862]
16. Ma X, Peddibhotla S, Zheng Y, Pan S, Mehta A, Moroni DG, Chen QY, Ma X, Burnett Jr JC, Malany S et al.. (2024) Discovery of small molecule guanylyl cyclase B receptor positive allosteric modulators. PNAS Nexus, 3 (6): pgae225. [PMID:38894878]
17. Maack T, Suzuki M, Almeida FA, Nussenzveig D, Scarborough RM, McEnroe GA, Lewicki JA. (1987) Physiological role of silent receptors of atrial natriuretic factor. Science, 238 (4827): 675-8. [PMID:2823385]
18. Martin FL, Sangaralingham SJ, Huntley BK, McKie PM, Ichiki T, Chen HH, Korinek J, Harders GE, Burnett Jr JC. (2012) CD-NP: a novel engineered dual guanylyl cyclase activator with anti-fibrotic actions in the heart. PLoS ONE, 7 (12): e52422. [PMID:23272242]
19. McKie PM, Cataliotti A, Huntley BK, Martin FL, Olson TM, Burnett Jr JC. (2009) A human atrial natriuretic peptide gene mutation reveals a novel peptide with enhanced blood pressure-lowering, renal-enhancing, and aldosterone-suppressing actions. J Am Coll Cardiol, 54 (11): 1024-32. [PMID:19729120]
20. Moffatt P, Thomas G, Sellin K, Bessette MC, Lafrenière F, Akhouayri O, St-Arnaud R, Lanctôt C. (2007) Osteocrin is a specific ligand of the natriuretic Peptide clearance receptor that modulates bone growth. J Biol Chem, 282 (50): 36454-62. [PMID:17951249]
21. Morishita Y, Sano T, Ando K, Saitoh Y, Kase H, Yamada K, Matsuda Y. (1991) Microbial polysaccharide, HS-142-1, competitively and selectively inhibits ANP binding to its guanylyl cyclase-containing receptor. Biochem Biophys Res Commun, 176 (3): 949-57. [PMID:1674870]
22. Murthy KS, Makhlouf GM. (1999) Identification of the G protein-activating domain of the natriuretic peptide clearance receptor (NPR-C). J Biol Chem, 274 (25): 17587-92. [PMID:10364194]
23. Nishida M, Miyamoto K, Abe S, Shimada M, Shimizu Y, Tsuji A, Yuasa K. (2021) Natriuretic peptide receptor-C releases and activates guanine nucleotide-exchange factor H1 in a ligand-dependent manner. Biochem Biophys Res Commun, 552: 9-16. [PMID:33740666]
24. Olson LJ, Lowe DG, Drewett JG. (1996) Novel natriuretic peptide receptor/guanylyl cyclase A-selective agonist inhibits angiotensin II- and forskolin-evoked aldosterone synthesis in a human zona glomerulosa cell line. Mol Pharmacol, 50 (2): 430-5. [PMID:8700153]
25. Shailubhai K, Comiskey S, Foss JA, Feng R, Barrow L, Comer GM, Jacob GS. (2013) Plecanatide, an oral guanylate cyclase C agonist acting locally in the gastrointestinal tract, is safe and well-tolerated in single doses. Dig Dis Sci, 58 (9): 2580-6. [PMID:23625291]
26. Shailubhai K, Palejwala V, Arjunan KP, Saykhedkar S, Nefsky B, Foss JA, Comiskey S, Jacob GS, Plevy SE. (2015) Plecanatide and dolcanatide, novel guanylate cyclase-C agonists, ameliorate gastrointestinal inflammation in experimental models of murine colitis. World J Gastrointest Pharmacol Ther, 6 (4): 213-22. [PMID:26558155]
27. Singh G, Kuc RE, Maguire JJ, Fidock M, Davenport AP. (2006) Novel snake venom ligand dendroaspis natriuretic peptide is selective for natriuretic peptide receptor-A in human heart: downregulation of natriuretic peptide receptor-A in heart failure. Circ Res, 99 (2): 183-90. [PMID:16778132]
28. Suga S, Nakao K, Hosoda K, Mukoyama M, Ogawa Y, Shirakami G, Arai H, Saito Y, Kambayashi Y, Inouye K. (1992) Receptor selectivity of natriuretic peptide family, atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide. Endocrinology, 130 (1): 229-39. [PMID:1309330]
29. Weber W, Fischli W, Hochuli E, Kupfer E, Weibel EK. (1991) Anantin--a peptide antagonist of the atrial natriuretic factor (ANF). I. Producing organism, fermentation, isolation and biological activity. J Antibiot, 44 (2): 164-71. [PMID:1849131]
30. Wyss DF, Lahm HW, Manneberg M, Labhardt AM. (1991) Anantin--a peptide antagonist of the atrial natriuretic factor (ANF). II. Determination of the primary sequence by NMR on the basis of proton assignments. J Antibiot, 44 (2): 172-80. [PMID:1826288]
NC-IUPHAR subcommittee and family contributors
Subcommittee members:
Adrian J. Hobbs (Co-chairperson)
Scott A. Waldman (Co-chairperson)
Doris Koesling
Michaela Kuhn
Lincoln R. Potter
Harald H.H.W. Schmidt
Johannes-Peter Stasch |
Other contributors:
Annie Beuve
Peter Brouckaert
John C. Burnett, Jr.
Andreas Friebe
John Garthwaite
Michael Russwurm |
How to cite this family page
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Fabbro D, Peach CJ, Gibb AJ, Kelly E, Mathie AA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Southan C, Davies JA et al. (2025) The Concise Guide to PHARMACOLOGY 2025/26: Catalytic receptors. Br J Pharmacol. 182: S259-S306.
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License
GC-D and GC-G have been reported to be activated intracellularly by guanylyl cyclase-activating protein 1 (GUCA1A, P43080) and guanylyl cyclase-activating protein 2 (GUCA1B, Q9UMX6). GC-D and GC-G may be activated by atmospheric levels of CO2 through the formation of intracellular bicarbonate ions [5,13]. GC-G may be activated at cooler temperatures (20-25°C) through apparent stabilisation of the dimer [4].