Nitric oxide (NO)-sensitive (soluble) guanylyl cyclase | Catalytic receptors

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Receptor guanylyl cyclase (RGC) family
Nitric oxide (NO)-sensitive (soluble) guanylyl cyclase

Nitric oxide (NO)-sensitive (soluble) guanylyl cyclase 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

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Nitric oxide (NO)-sensitive (soluble) guanylyl cyclase (GTP diphosphate-lyase (cyclising)), E.C. 4.6.1.2, is a heterodimer comprising a β₁ subunit and one of two alpha subunits (α₁, α₂) giving rise to two functional isoforms, GC-1 (α₁β₁) and GC-2 (α₂β₁) [13,19]. A haem group is associated with the β subunit and is the target for the endogenous ligand NO, and, potentially, carbon monoxide [5].

Receptors

1289

Targets of relevance to immunopharmacology are highlighted in blue

Complexes

GC-1 (Guanylyl cyclase, α₁β₁) C Show summary »« Hide summary More detailed page go icon to follow link

GC-2 (Guanylyl cyclase, α₂β₁) C Show summary »« Hide summary More detailed page go icon to follow link

Receptors and Subunits

Guanylyl cyclase α₁ subunit C Show summary »« Hide summary

Target Id	1288
Nomenclature	Guanylyl cyclase α₁ subunit
Previous and unofficial names	GCS-alpha-1 \| GCS-alpha-3 \| guanylate cyclase 1, soluble, alpha 3 \| SGC \| soluble guanylate cyclase \| soluble guanylate cyclase large subunit \| alpha 1 sGC \| GC-SA3 \| guanylate cyclase, soluble, alpha 1 (GTP pyrophosphate - lyase) \| guanylate cyclase 1 \| GUCY1A3 \| guanylate cyclase 1 soluble subunit alpha \| Gucy1a3 \| guanylate cyclase 1 soluble subunit alpha 3 \| guanylate cyclase 1, soluble, alpha 1
Complexes	GC-1 (Guanylyl cyclase, α₁β₁)
Genes	GUCY1A1 (Hs), Gucy1a1 (Mm), Gucy1a1 (Rn)
Ensembl ID	ENSG00000164116 (Hs), ENSMUSG00000033910 (Mm), ENSRNOG00000012302 (Rn)
UniProtKB AC	Q02108 (Hs), Q9ERL9 (Mm), P19686 (Rn)

Guanylyl cyclase α₂ subunit C Show summary »« Hide summary

Target Id	1289
Nomenclature	Guanylyl cyclase α₂ subunit
Previous and unofficial names	GCS-alpha-2 \| guanylate cyclase 1, soluble, alpha 2 \| GC-SA2 \| guanylate cyclase 1
Complexes	GC-2 (Guanylyl cyclase, α₂β₁)
Genes	GUCY1A2 (Hs), Gucy1a2 (Mm), Gucy1a2 (Rn)
Ensembl ID	ENSG00000152402 (Hs), ENSMUSG00000041624 (Mm), ENSRNOG00000029876 (Rn)
UniProtKB AC	P33402 (Hs), Q9WVI4 (Rn)

Guanylyl cyclase β₁ subunit C Show summary »« Hide summary

Target Id	1290
Nomenclature	Guanylyl cyclase β₁ subunit
Previous and unofficial names	guanylate cyclase 1 soluble beta 3 \| guanylate cyclase soluble subunit beta-1 \| guanylate cyclase soluble subunit beta-3 \| guanylate cyclase, soluble, beta 1 \| guanylate cyclase, soluble, beta 1, (GTP pyrophosphate - lyase) \| Gucy1b1 \| soluble guanylate cyclase small subunit \| beta 1 sGC \| GC-SB3 \| guanylate cyclase 1 \| GUCY1B3 \| guanylate cyclase 1 soluble subunit beta \| Gucy1b3 \| guanylate cyclase 1 soluble subunit beta 3 \| guanylate cyclase 1, soluble, beta 1
Complexes	GC-1 (Guanylyl cyclase, α₁β₁) GC-2 (Guanylyl cyclase, α₂β₁)
Genes	GUCY1B1 (Hs), Gucy1b1 (Mm), Gucy1b1 (Rn)
Ensembl ID	ENSG00000061918 (Hs), ENSMUSG00000028005 (Mm), ENSRNOG00000012060 (Rn)
UniProtKB AC	Q02153 (Hs), O54865 (Mm), P20595 (Rn)

Guanylyl cyclase β₂ subunit C Show summary »« Hide summary

Target Id	1291
Nomenclature	Guanylyl cyclase β₂ subunit
Previous and unofficial names	GCS-beta-2 \| guanylate cyclase 1 soluble beta 2 \| Guanylate cyclase soluble beta 2 (GTP pyrophosphate - lyase) \| guanylate cyclase soluble subunit beta-2 \| Gucy1b2a \| Gucy1b2b \| soluble guanylate cyclase beta 2a \| soluble guanylate cyclase beta 2b \| GC-SB2 \| guanylate cyclase 1, soluble, beta 2 (pseudogene) \| guanylate cyclase 1
Genes	GUCY1B2 (Hs), Gucy1b2 (Mm), Gucy1b2 (Rn)
Ensembl ID	ENSG00000123201 (Hs), ENSMUSG00000021933 (Mm), ENSRNOG00000009440 (Rn)
UniProtKB AC	O75343 (Hs), P22717 (Rn)

Comments

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References

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1. Buys ES, Zimmer DP, Chickering J, Graul R, Chien YT, Profy A, Hadcock JR, Masferrer JL, Milne GT. (2018) Discovery and development of next generation sGC stimulators with diverse multidimensional pharmacology and broad therapeutic potential. Nitric Oxide, 78: 72-80. [PMID:29859918]

2. Feelisch M, Kotsonis P, Siebe J, Clement B, Schmidt HH. (1999) The soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a] quinoxalin-1-one is a nonselective heme protein inhibitor of nitric oxide synthase and other cytochrome P-450 enzymes involved in nitric oxide donor bioactivation. Mol Pharmacol, 56 (2): 243-53. [PMID:10419542]

3. Follmann M, Ackerstaff J, Redlich G, Wunder F, Lang D, Kern A, Fey P, Griebenow N, Kroh W, Becker-Pelster EM et al.. (2017) Discovery of the Soluble Guanylate Cyclase Stimulator Vericiguat (BAY 1021189) for the Treatment of Chronic Heart Failure. J Med Chem, 60 (12): 5146-5161. [PMID:28557445]

4. Friebe A, Müllershausen F, Smolenski A, Walter U, Schultz G, Koesling D. (1998) YC-1 potentiates nitric oxide- and carbon monoxide-induced cyclic GMP effects in human platelets. Mol Pharmacol, 54 (6): 962-7. [PMID:9855623]

5. Friebe A, Schultz G, Koesling D. (1996) Sensitizing soluble guanylyl cyclase to become a highly CO-sensitive enzyme. EMBO J, 15 (24): 6863-8. [PMID:9003762]

6. Galle J, Zabel U, Hübner U, Hatzelmann A, Wagner B, Wanner C, Schmidt HH. (1999) Effects of the soluble guanylyl cyclase activator, YC-1, on vascular tone, cyclic GMP levels and phosphodiesterase activity. Br J Pharmacol, 127 (1): 195-203. [PMID:10369473]

7. Garthwaite J, Southam E, Boulton CL, Nielsen EB, Schmidt K, Mayer B. (1995) Potent and selective inhibition of nitric oxide-sensitive guanylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. Mol Pharmacol, 48 (2): 184-8. [PMID:7544433]

8. Hahn MG, Lampe T, El Sheikh S, Griebenow N, Woltering E, Schlemmer KH, Dietz L, Gerisch M, Wunder F, Becker-Pelster EM et al.. (2021) Discovery of the Soluble Guanylate Cyclase Activator Runcaciguat (BAY 1101042). J Med Chem, 64 (9): 5323-5344. [PMID:33872507]

9. Horst BG, Yokom AL, Rosenberg DJ, Morris KL, Hammel M, Hurley JH, Marletta MA. (2019) Allosteric activation of the nitric oxide receptor soluble guanylate cyclase mapped by cryo-electron microscopy. Elife, 8. [PMID:31566566]

10. Kang Y, Liu R, Wu JX, Chen L. (2019) Structural insights into the mechanism of human soluble guanylate cyclase. Nature, 574 (7777): 206-210. [PMID:31514202]

11. Ko FN, Wu CC, Kuo SC, Lee FY, Teng CM. (1994) YC-1, a novel activator of platelet guanylate cyclase. Blood, 84 (12): 4226-33. [PMID:7527671]

12. Olesen SP, Drejer J, Axelsson O, Moldt P, Bang L, Nielsen-Kudsk JE, Busse R, Mülsch A. (1998) Characterization of NS 2028 as a specific inhibitor of soluble guanylyl cyclase. Br J Pharmacol, 123 (2): 299-309. [PMID:9489619]

13. Russwurm M, Behrends S, Harteneck C, Koesling D. (1998) Functional properties of a naturally occurring isoform of soluble guanylyl cyclase. Biochem J, 335 ( Pt 1): 125-30. [PMID:9742221]

14. Schindler U, Strobel H, Schönafinger K, Linz W, Löhn M, Martorana PA, Rütten H, Schindler PW, Busch AE, Sohn M et al.. (2006) Biochemistry and pharmacology of novel anthranilic acid derivatives activating heme-oxidized soluble guanylyl cyclase. Mol Pharmacol, 69 (4): 1260-8. [PMID:16332991]

15. Stasch JP, Becker EM, Alonso-Alija C, Apeler H, Dembowsky K, Feurer A, Gerzer R, Minuth T, Perzborn E, Pleiss U et al.. (2001) NO-independent regulatory site on soluble guanylate cyclase. Nature, 410 (6825): 212-5. [PMID:11242081]

16. Stasch JP, Hobbs AJ. (2009) NO-independent, haem-dependent soluble guanylate cyclase stimulators. Handb Exp Pharmacol, (191): 277-308. [PMID:19089334]

17. Stasch JP, Schmidt P, Alonso-Alija C, Apeler H, Dembowsky K, Haerter M, Heil M, Minuth T, Perzborn E, Pleiss U et al.. (2002) NO- and haem-independent activation of soluble guanylyl cyclase: molecular basis and cardiovascular implications of a new pharmacological principle. Br J Pharmacol, 136 (5): 773-83. [PMID:12086987]

18. Tobin JV, Zimmer DP, Shea C, Germano P, Bernier SG, Liu G, Long K, Miyashiro J, Ranganath S, Jacobson S et al.. (2018) Pharmacological Characterization of IW-1973, a Novel Soluble Guanylate Cyclase Stimulator with Extensive Tissue Distribution, Antihypertensive, Anti-Inflammatory, and Antifibrotic Effects in Preclinical Models of Disease. J Pharmacol Exp Ther, 365 (3): 664-675. [PMID:29643251]

19. Zabel U, Weeger M, La M, Schmidt HH. (1998) Human soluble guanylate cyclase: functional expression and revised isoenzyme family. Biochem J, 335 ( Pt 1): 51-7. [PMID:9742212]

NC-IUPHAR subcommittee and family contributors

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Subcommittee members:

Adrian J. Hobbs (Co-chairperson)
Professor of Cardiovascular Pharmacology
William Harvey Research Institute
Heart Centre (1st Floor)
Barts & The London
School of Medicine & Dentistry
Queen Mary University of London
Charterhouse Square
London EC1M 6BQ
UK

Scott A. Waldman (Co-chairperson)
Department of Pharmacology and Experimental Therapeutics
Thomas Jefferson University
Philadelphia
Pennsylvania, USA

John C. Burnett, Jr.
(Past contributor)
Division of Cardiovascular Disease
Mayo Clinic
Rochester
MN
USA

John Garthwaite
(Past contributor)
Wolfson Institute for Biomedical Research
University College London
Gower Street
London WC1E 6BT
UK

Doris Koesling
Institut für Pharmakologie und Toxikologie
Medizinische Fakultät
Ruhr-Universität Bochum
44780 Bochum, Germany

Michaela Kuhn
Physiologisches Institut der Universität Würzburg
Würzburg
Germany

Lincoln R. Potter
Molecular Biology and Biophysics
University of Minnesota
Minneapolis, MN 55455, USA

Michael Russwurm
(Past contributor)
Department of Pharmacology and Toxicology
Ruhr University Bochum
Bochum, Germany

Harald H.H.W. Schmidt
Department of Pharmacology
Maastricht University
Maastricht
The Netherlands

Johannes-Peter Stasch
Cardiovascular Research
Bayer AG
Wuppertal, Germany

Other contributors:

Annie Beuve
Department of Pharmacology Physiology and Neuroscience
Rutgers Medical School
New Jersey, USA

Peter Brouckaert
Laboratory for Molecular Pathology and Experimental Therapy
Inflammation Research Center
Ghent, Belgium

Andreas Friebe
Physiologisches Institut
Röntgenring 9
Würzburg, Germany

How to cite this family page

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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.