Skip to main content
SpringerLink
Log in

Isoforms of NO-sensitive guanylyl cyclase

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

By the formation of cGMP the NO-sensitive guanylyl cyclase plays a key role within the NO/cGMP signaling cascade involved in vascular regulation and neurotransmission. The prosthetic heme group of the enzyme acts as the NO sensor, and binding of NO induces conformational changes leading to an up to 200-fold activation of the enzyme. The unexpected fast dissociation half-life of NO of a few seconds is fast enough to account for the deactivation of the enzyme in biological systems. YC-1 and its analogues acting as NO sensitizers uncovered a new pharmacologically and conceivably physiologically relevant regulatory principle of the enzyme.

Two existing isoforms of the heterodimeric guanylyl cyclase (α1β1, α2β1) are known that are functionally indistinguishable. Up to now, the NO-sensitive guanylyl cyclase has been considered as a soluble enzyme. However, recent evidence about the α2β1 isoform interacting with a PDZ domain of the postsynaptic scaffold protein PSD-95 suggests that the α2 subunit directs a membrane association of this isoform. The interaction with PSD-95 locates the α2β1 isoform in close proximity to the NO-generating NO synthase thereby enabling the NO sensor to respond to locally raised NO concentrations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Koesling D, Herz J, Gausepohl H, Niroomand F, Hinsch KD, Mulsch A, Bohme E, Schultz G, Frank R: The primary structure of the 70 kDa subunit of bovine soluble guanylate cyclase. FEBS Lett 239: 29–34, 1988

    Google Scholar 

  2. Nakane M, Saheki S, Kuno T, Ishii K, Murad F: Molecular cloning of a cDNA coding for 70 kilodalton subunit of soluble guanylate cyclase from rat lung. Biochem Biophys Res Commun 157: 1139–1147, 1988

    Google Scholar 

  3. Koesling D, Harteneck C, Humbert P, Bosserhoff A, Frank R, Schultz G, Bohme E: The primary structure of the larger subunit of soluble guanylyl cyclase from bovine lung. Homology between the two subunits of the enzyme. FEBS Lett 266: 128–132, 1990

    Google Scholar 

  4. Nakane M, Arai K, Saheki S, Kuno T, Buechler W, Murad F: Molecular cloning and expression of cDNAs coding for soluble guanylate cyclase from rat lung. J Biol Chem 265: 16841–16845, 1990

    Google Scholar 

  5. Yuen PS, Potter LR, Garbers DL: A new form of guanylyl cyclase is preferentially expressed in rat kidney. Biochemistry 29: 10872–10878, 1990

    Google Scholar 

  6. Harteneck C, Wedel B, Koesling D, Malkewitz J, Bohme E, Schultz G: Molecular cloning and expression of a new α-subunit of soluble guanylyl cyclase. Interchangeability of the α-subunits of the enzyme. FEBS Lett 292: 217–222, 1991

    Google Scholar 

  7. Zabel U, Weeger M, La M, Schmidt HH: Human soluble guanylate cyclase: Functional expression and revised isoenzyme family. Biochem J 335: 51–57, 1998

    Google Scholar 

  8. Harteneck C, Koesling D, Soling A, Schultz G, Bohme E: Expression of soluble guanylyl cyclase. Catalytic activity requires two enzyme subunits. FEBS Lett 272: 221–223, 1990

    Google Scholar 

  9. Buechler WA, Nakane M, Murad F: Expression of soluble guanylate cyclase activity requires both enzyme subunits. Biochem Biophys Res Commun 174: 351–357, 1991

    Google Scholar 

  10. Gupta G, Azam M, Yang L, Danziger RS: The β2 subunit inhibits stimulation of the α1/β1 form of soluble guanylyl cyclase by nitric oxide. Potential relevance to regulation of blood pressure. J Clin Invest 100: 1488–1492, 1997

    Google Scholar 

  11. Wedel B, Harteneck C, Foerster J, Friebe A, Schultz G, Koesling D: Functional domains of soluble guanylyl cyclase. J Biol Chem 270: 24871–24875, 1995

    Google Scholar 

  12. Zhang G, Liu Y, Ruoho AE, Hurley JH: Structure of the adenylyl cyclase catalytic core. Nature 386: 247–253, 1997

    Google Scholar 

  13. Tesmer JJ, Sunahara RK, Gilman AG, Sprang SR: Crystal structure of the catalytic domains of adenylyl cyclase in a complex with Gsα.GTPγS. Science 278: 1907–1916, 1997

    Google Scholar 

  14. Sunahara RK, Beuve A, Tesmer JJ, Sprang SR, Garbers DL, Gilman AG: Exchange of substrate and inhibitor specificities between adenylyl and guanylyl cyclases. J Biol Chem 273: 16332–16338, 1998

    Google Scholar 

  15. Wilson EM, Chinkers M: Identification of sequences mediating guanylyl cyclase dimerization. Biochemistry 34: 4696–4701, 1995

    Google Scholar 

  16. Schelvis JP, Zhao Y, Marletta MA, Babcock GT: Resonance raman characterization of the heme domain of soluble guanylate cyclase. Biochemistry 37: 16289–16297, 1998

    Google Scholar 

  17. Wedel B, Humbert P, Harteneck C, Foerster J, Malkewitz J, Bohme E, Schultz G, Koesling D: Mutation of His-105 in the β1 subunit yields a nitric oxide-insensitive form of soluble guanylyl cyclase. Proc Natl Acad Sci USA 91: 2592–2596, 1994

    Google Scholar 

  18. Russwurm M, Behrends S, Harteneck C, Koesling D: Functional properties of a naturally occurring isoform of soluble guanylyl cyclase. Biochem J 335: 125–130, 1998

    Google Scholar 

  19. Gerzer R, Hofmann F, Schultz G: Purification of a soluble, sodiumnitroprusside-stimulated guanylate cyclase from bovine lung. Eur J Biochem 116: 479–486, 1981

    Google Scholar 

  20. Humbert P, Niroomand F, Fischer G, Mayer B, Koesling D, Hinsch KD, Gausepohl H, Frank R, Schultz G, Bohme E: Purification of soluble guanylyl cyclase from bovine lung by a new immunoaffinity chromatographic method. Eur J Biochem 190: 273–278, 1990

    Google Scholar 

  21. Stone JR, Marletta MA: Heme stoichiometry of heterodimeric soluble guanylate cyclase. Biochemistry 34: 14668–14674, 1995

    Google Scholar 

  22. Gerzer R, Bohme E, Hofmann F, Schultz G: Soluble guanylate cyclase purified from bovine lung contains heme and copper. FEBS Lett 132: 71–74, 1981

    Google Scholar 

  23. Tomita T, Tsuyama S, Imai Y, Kitagawa T: Purification of bovine soluble guanylate cyclase and ADP-ribosylation on its small subunit by bacterial toxins. J Biochem (Tokyo) 122: 531–536, 1997

    Google Scholar 

  24. Brandish PE, Buechler W, Marletta MA: Regeneration of the ferrous heme of soluble guanylate cyclase from the nitric oxide complex: Acceleration by thiols and oxyhemoglobin. Biochemistry 37: 16898–16907, 1998

    Google Scholar 

  25. Stone JR, Marletta MA: Soluble guanylate cyclase from bovine lung: Activation with nitric oxide and carbon monoxide and spectral characterization of the ferrous and ferric states. Biochemistry 33: 5636–5640, 1994

    Google Scholar 

  26. Ignarro LJ, Wood KS, Wolin MS: Activation of purified soluble guanylate cyclase by protoporphyrin IX. Proc Natl Acad Sci USA 79: 2870–2873, 1982

    Google Scholar 

  27. Friebe A, Schultz G, Koesling D: Sensitizing soluble guanylyl cyclase to become a highly CO-sensitive enzyme. Embo J 15: 6863–6868, 1996

    Google Scholar 

  28. Foerster J, Harteneck C, Malkewitz J, Schultz G, Koesling D: A functional heme-binding site of soluble guanylyl cyclase requires intact Ntermini of α1 and β1 subunits. Eur J Biochem 240: 380–386, 1996

    Google Scholar 

  29. Zhao Y, Schelvis JP, Babcock GT, Marletta MA: Identification of histidine 105 in the β1 subunit of soluble guanylate cyclase as the heme proximal ligand. Biochemistry 37: 4502–4509, 1998

    Google Scholar 

  30. Kharitonov VG, Sharma VS, Magde D, Koesling D: Kinetics of nitric oxide dissociation from five-and six-coordinate nitrosyl hemes and heme proteins, including soluble guanylate cyclase. Biochemistry 36: 6814–6818, 1997

    Google Scholar 

  31. Bellamy TC, Wood J, Goodwin DA, Garthwaite J: Rapid desensitization of the nitric oxide receptor, soluble guanylyl cyclase, underlies diversity of cellular cGMP responses. Proc Natl Acad Sci USA 97: 2928–2933, 2000

    Google Scholar 

  32. Kharitonov VG, Russwurm M, Magde D, Sharma VS, Koesling D: Dissociation of nitric oxide from soluble guanylate cyclase. Biochem Biophys Res Commun 239: 284–286, 1997

    Google Scholar 

  33. Margulis A, Sitaramayya A: Rate of deactivation of nitric oxide-stimulated soluble guanylate cyclase: Influence of nitric oxide scavengers and calcium. Biochemistry 39: 1034–1039, 2000

    Google Scholar 

  34. Bellamy TC, Garthwaite J: Sub-second kinetics of the nitric oxide receptor, soluble guanylyl cyclase, in intact cerebellar cells. J Biol Chem 9: 4287–4292, 2000

    Google Scholar 

  35. Garthwaite J, Southam E, Boulton CL, Nielsen EB, Schmidt K, Mayer B: 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: 184–188, 1995

    Google Scholar 

  36. Brunner F, Schmidt K, Nielsen EB, Mayer B: Novel guanylyl cyclase inhibitor potently inhibits cyclic GMP accumulation in endothelial cells and relaxation of bovine pulmonary artery. J Pharmacol Exp Ther 277: 48–53, 1996

    Google Scholar 

  37. Abi-Gerges N, Hove-Madsen L, Fischmeister R, Mery PF: A comparative study of the effects of three guanylyl cyclase inhibitors on the Ltype Ca2+ and muscarinic K+ currents in frog cardiac myocytes. Br J Pharmacol 121: 1369–1377, 1997

    Google Scholar 

  38. Schrammel A, Behrends S, Schmidt K, Koesling D, Mayer B: Characterization of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one as a heme-site inhibitor of nitric oxide-sensitive guanylyl cyclase. Mol Pharmacol 50: 1–5, 1996

    Google Scholar 

  39. Koesling D, Friebe A: Soluble guanylyl cyclase: Structure and regulation. Rev Physiol Biochem Pharmacol 135: 41–65, 1999

    Google Scholar 

  40. Wu CC, Ko FN, Kuo SC, Lee FY, Teng CM: YC-1 inhibited human platelet aggregation through NO-independent activation of soluble guanylate cyclase. Br J Pharmacol 116: 1973–1978, 1995

    Google Scholar 

  41. Teng CM, Wu CC, Ko FN, Lee FY, Kuo SC: YC-1, a nitric oxide-independent activator of soluble guanylate cyclase, inhibits platelet-rich thrombosis in mice. Eur J Pharmacol 320: 161–166, 1997

    Google Scholar 

  42. Mulsch A, Bauersachs J, Schafer A, Stasch JP, Kast R, Busse R: Effect of YC-1, an NO-independent, superoxide-sensitive stimulator of soluble guanylyl cyclase, on smooth muscle responsiveness to nitrovasodilators. Br J Pharmacol 120: 681–689, 1997

    Google Scholar 

  43. Wegener JW, Gath I, Forstermann U, Nawrath H: Activation of soluble guanylyl cyclase by YC-1 in aortic smooth muscle but not in ventricular myocardium from rat. Br J Pharmacol 122: 1523–1529, 1997

    Google Scholar 

  44. Friebe A, Koesling D: Mechanism of YC-1-induced activation of soluble guanylyl cyclase. Mol Pharmacol 53: 123–127, 1998

    Google Scholar 

  45. Friebe A, Mullershausen F, Smolenski A, Walter U, Schultz G, Koesling D: YC-1 potentiates nitric oxide-and carbon monoxide-induced cyclic GMP effects in human platelets. Mol Pharmacol 54: 962–967, 1998

    Google Scholar 

  46. Galle J, Zabel U, Hubner U, Hatzelmann A, Wagner B, Wanner C, Schmidt HH: Effects of the soluble guanylyl cyclase activator, YC-1, on vascular tone, cyclic GMP levels and phosphodiesterase activity. Br J Pharmacol 127: 195–203, 1999

    Google Scholar 

  47. Stasch JP, Becker EM, Alonso-Alija C, Apeler H, Dembowsky K, Feurer A, Gerzer R, Minuth T, Perzborn E, Pleiss U, Schroder H, Schroeder W, Stahl E, Steinke W, Straub A, Schramm M: NO-independent regulatory site on soluble guanylate cyclase. Nature 410: 212–215, 2001

    Google Scholar 

  48. Budworth J, Meillerais S, Charles I, Powell K: Tissue distribution of the human soluble guanylate cyclases. Biochem Biophys Res Commun 263: 696–701, 1999

    Google Scholar 

  49. Gibb BJ, Garthwaite J: Subunits of the nitric oxide receptor, soluble guanylyl cyclase, expressed in rat brain. Eur J Neurosci 13: 539–544, 2001

    Google Scholar 

  50. Furuyama T, Inagaki S, Takagi, H: Localizations of α1 and β1 subunits of soluble guanylate cyclase in the rat brain. Brain Res Mol Brain Res 20: 335–344, 1993

    Google Scholar 

  51. Russwurm M, Wittau N, Koesling D: Guanylyl cyclase/PSD-95 interaction: Targeting of the NO-sensitive α2β1 guanylyl cyclase to synaptic membranes. J Biol Chem 276: 44647–44652, 2001

    Google Scholar 

  52. Craven SE, Bredt DS: PDZ proteins organize synaptic signaling pathways. Cell 93: 495–498, 1998

    Google Scholar 

  53. Garner CC, Nash J, Huganir RL: PDZ domains in synapse assembly and signalling. Trends Cell Biol 10: 274–280, 2000

    Google Scholar 

  54. Sheng M, Pak DT: Ligand-gated ion channel interactions with cytoskeletal and signaling proteins. Annu Rev Physiol 62: 755–778, 2000

    Google Scholar 

  55. Kornau HC, Schenker LT, Kennedy MB, Seeburg PH: Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science 269: 1737–1740, 1995

    Google Scholar 

  56. Niethammer M, Kim E, Sheng M: Interaction between the C terminus of NMDA receptor subunits and multiple members of the PSD-95 family of membrane-associated guanylate kinases. J Neurosci 16: 2157–2163, 1996

    Google Scholar 

  57. Brenman JE, Chao DS, Gee SH, McGee AW, Craven SE, Santillano DR, Wu Z, Huang F, Xia H, Peters MF, Froehner SC, Bredt DS: Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and a1-syntrophin mediated by PDZ domains. Cell 84: 757–767, 1996

    Google Scholar 

  58. Christopherson KS, Hillier BJ, Lim WA, Bredt DS: PSD-95 assembles a ternary complex with the N-methyl-D-aspartic acid receptor and a bivalent neuronal NO synthase PDZ domain. J Biol Chem 274: 27467–27473, 1999

    Google Scholar 

Download references

Authors
  1. Michael Russwurm
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Doris Koesling
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Russwurm, M., Koesling, D. Isoforms of NO-sensitive guanylyl cyclase. Mol Cell Biochem 230, 159–164 (2002). https://doi.org/10.1023/A:1014252309493

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1014252309493

Search

Navigation