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 functionally indistinguishable 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].

ODQ also shows activity at other haem-containing proteins [2], while YC-1 may also inhibit cGMP-hydrolysing phosphodiesterases [4,6].

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]

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. Division of Cardiovascular Disease Mayo Clinic Rochester MN USA John Garthwaite 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 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