Mechanisms of regulation and functions of guanylyl cyclases

  • D. C. Foster
  • B. J. Wedel
  • S. W. Robinson
  • D. L. Garbers
Part of the Reviews of Physiology, Biochemistry and Pharmacology book series (volume 135)


Although enormous progress in understanding guanylyl cyclase structure and regulation has been recently made, many questions remain. There are now numerous guanylyl cyclase sequences, and signature sequences for discrete domains within these molecules can be identified. The majority of the guanylyl cyclases identified, however are orphan receptors. A primary goal, therefore, is the identification of ligands for the numerous orphan receptor guanylyl cyclases. Identification of these molecules may provide insight into systems such as vision and olfaction among others. In addition, it will be of interest to identify guanylyl cyclase regulatory proteins. These molecules may provide insight into guanylyl cyclase regulation and provide targets for other signaling pathways to modulate guanylyl cyclase activity. Finally, the information gained from structural studies of adenylyl cyclase has shed new light on the guanylyl cyclase catalytic domain, and raised the possibility of a previously unidentified regulatory pocket within the catalytic domain. Understanding the role of this potential regulatory region may provide new insight into not only guanylyl cyclase regulation, but numerous physiological processes.


Atrial Natriuretic Peptide Adenylyl Cyclase Guanylate Cyclase Guanylyl Cyclase Soluble Guanylate Cyclase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



nitric oxide


carbon monoxide


atrial natriuretic peptide




adenosine 5′-O-thiotriphosphate

2′d3′ AMP

2′-deoxyadenosine 3′-monophosphate


soluble guanylyl cyclase


membrane guanylyl cyclase


adenylyl cyclase


heat-stable enterotoxin of E. coli


protein kinase C


guanylyl cyclase A-G


transmembrane domain


extracellular domain


kinase homology domain


dimerization domain


cyclase homology domain


heme binding domain




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  1. Aparicio JG, Applebury ML (1996) The photoreceptor guanylate cyclase is an autophosphorylating protein kinase. J Biol Chem 271:27083–27089Google Scholar
  2. Baude EJ, Arora VK, Yu S, Garbers DL, Wedel BJ (1997) The cloning of a Caenorhabditis elegans guanylyl cyclase and the construction of a ligand-sensitive mammalian/nematode chimeric receptor. J Biol Chem 272:16035–16039Google Scholar
  3. Bentley JK, Tubb DJ, Garbers DL (1986) Receptor-mediated activation of spermatozoan guanylate cyclase. J Biol Chem 261:14859–14862Google Scholar
  4. Chang C, Kohse KP, Chang B, Hirata M, Jiang B, Douglas JE, Murad F (1990) Characterization of ATP-stimulated guanylate cyclase activation in rat lung membranes. Biochim Biophys Acta 1052:159–165Google Scholar
  5. Chinkers M, Singh S, Garbers DL (1991) Adenine nucleotides are required for activation of rat atrial natriuretic peptide receptor/guanylyl cyclase expressed in a baculovirus system. J Biol Chem 266:4088–4093Google Scholar
  6. Chinkers M, Garbers DL (1989) The protein kinase domain of the ANP receptor is required for signaling. Science 245:1392–1394Google Scholar
  7. Chinkers M, Wilson EM (1992) Ligand-independent oligomerization of natriuretic peptide receptors:Identification of heteromeric receptors and a dominant negative mutant. J Biol Chem 267:18589–18597Google Scholar
  8. Cooper N, Liu L, Yoshida A, Pozdnyakov N, Margulis A, Sitaramayya A (1996) The bovine rod outer segment guanylate cyclase, ROS-GC1, is present in both outer and synaptic layers of the retina. J Mol Neurosci 6:211–222Google Scholar
  9. Crane JK, Shanks KL (1996) Phosphorylation and activation of the intestinal guanylyl cyclase receptor for Escherichia coli heat-stable toxin by protein kinase C. Mol Cell Biochem 165:111–120Google Scholar
  10. Dessauer CW, Gilman AG (1997) The catalytic mechanism of mammalian adenylyl cyclase. Equilibrium binding and kinetic analysis of P-site inhibition. J Biol Chem 272:27787–27795Google Scholar
  11. Dizhoor AM, Lowe DG, Olshevskaya EV, Laura RP, Hurley JB (1994) The human photoreceptor membrane guanylyl cyclase, RetGC, is present in outer segments and is regulated by calcium and a soluble activator. Neuron 12:1345–1352Google Scholar
  12. Drewett JG, Garbers DL (1994) The family of guanylyl cyclase receptors: Their ligands and functions. Endocrine Reviews 15:135–162Google Scholar
  13. Fenrick R, McNicoll N, De Lean A (1996) Glycosylation is critical for natriuretic peptide receptor-B function. Mol Cell Biochem 165:103–109Google Scholar
  14. Foerster J, Harteneck C, Malkewitz J, Schultz G, Koesling D (1996) A functional heme-binding site of soluble guanylyl cyclase requires intact N-termini of alpha 1 and beta 1 subunits. Eur J Biochem 240:380–386Google Scholar
  15. Foster DC, Garbers DL (1998) Dual role for adenine nucleotides in the regulation of the atrial natriuretic peptide receptor, guanylyl cyclase-A. J Biol Chem 273:16311–16318Google Scholar
  16. Friebe A, Schultz G, Koesling D (1996) Sensitizing soluble guanylyl cyclase to become a highly Co-sensitive enzyme. EMBO J 15:6863–6868Google Scholar
  17. Friebe A, Koesling D (1998) Mechanism of YC-1-induced activation of soluble guanylyl cyclase. Mol Pharmacol 53:123–127Google Scholar
  18. Garbers DL (1979) Purification of soluble guanylate cyclase from rat lung. J Biol Chem 254:240–243Google Scholar
  19. Garbers DL, Koesling D, Schultz G (1994) Guanylyl cyclase receptors. Mol Biol Cell 5:1–5Google Scholar
  20. Garbers DL, Lowe DG (1994) Guanylyl cyclase receptors. J Biol Chem 269:30741–30744Google Scholar
  21. 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 48:184–188Google Scholar
  22. Gerzer R, Böhme E, Hofmann F, Schultz G (1981) Soluble guanylate cyclase purified from bovine lung contains heme and copper. FEBS Lett 132:71–74Google Scholar
  23. Goraczniak RM, Duda T, Sharma RK (1992) A structural motif that defines the ATP-regulatory module of guanylate cyclase in atrial natriuretic factor signalling. Biochem J 282:533–537Google Scholar
  24. Gow AJ, Stamler JS (1998) Reactions between nitric oxide and haemoglobin under physiological conditions. Nature 391:169–173Google Scholar
  25. Harteneck C, Koesling D, Soling A, Schultz G, Bohme E (1990) Expression of soluble guanylate cyclase:catalytic activity requires two enzyme subunits. FEBS Lett 272:221–223Google Scholar
  26. Hobbs AJ (1997) Soluble guanylate cyclase:the forgotten sibling. Trends Pharmacol Sci 18:484–491Google Scholar
  27. Humbert P, Niroomand F, Fischer G, Mayer B, Koesling D, Hinsch K, Gausepohl H, Frank R, Schultz G, Böhme E (1990) Purification of soluble guanylyl cyclase from bovine lung by a new immunoaffinity chromatographic method. Eur J Biochem 190:273–278Google Scholar
  28. Ignarro LJ, Wood KS, Wolin MS (1982) Activation of purified soluble guanylate cyclase by protoporphyrin IX. Proc Natl Acad Sci USA 79:2870–2873Google Scholar
  29. Ignarro LJ, Wood KS, Wolin MS (1984) Regulation of purified soluble guanylate cyclase by porphyrins and metalloporphyrins:a unifying concept. Adv Cyclic Nucleo Res 17:267–274Google Scholar
  30. Itakura M, Iwashina M, Mizuno T, Ito T, Hagiwara H, Hirose S (1994) Mutational analysis of disulfide bridges in the type C atrial natriuretic peptide receptor. J Biol Chem 269:8314–8318Google Scholar
  31. Kamisaki Y, Saheki S, Nakane M, Palmieri JA, Kuno T, Chang BY, Waldman SA, Murad F (1986) Soluble guanylate cyclase from rat lung exists as a heterodimer. J Biol Chem 261:7236–7241Google Scholar
  32. Kelsell RE, Gregory-Evans K, Payne AM, Perrault I., Kaplan J., Yang RB, Garbers DL, Bird AC, Moore AT, Hunt DM (1998) Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant cone-rod dystrophy. Hum Mol Genet 7:1179–1184Google Scholar
  33. Kharitonov VG, Sharma VS, Pilz RB, Magde D, Koesling D (1995) Basis of guanylate cyclase activation by carbon monoxide. Proc Natl Acad Sci USA 92:2568–2571Google Scholar
  34. Kishimoto I, Dubois SK, Garbers DL (1996) The heart communicates with the kidney exclusively through the guanylyl cyclase-A receptor:acute handling of sodium and water in response to volume expansion. Proc Natl Acad Sci USA 93:6215–6219Google Scholar
  35. Koller KJ, Lipari MT, Goeddel DV (1993) Proper glycosylation and phosphorylation of the type A natriuretic peptide receptor are required for hormone-stimulated guanylyl cyclase activity. J Biol Chem 268:5997–6003Google Scholar
  36. Kurose H, Inagami T, Ui M (1987) Participation of adenosine 5′-triphosphate in the activation of membrane-bound guanylate cyclase by the atrial natriuretic factor. FEBS Letts 219:375–379Google Scholar
  37. Landschulz WH, Johnson PF, McKnight SL (1988) The leucine zipper:a hypothetical structure common to a new class of DNA binding proteins. Science 240:1759–1764Google Scholar
  38. Laura RP, Dizhoor AM, Hurley JB (1996) The membrane guanylyl cyclase, retinal guanylyl cyclase-1, is activated through its intracellular domain. J Biol Chem 271:11646–11651Google Scholar
  39. Liu X, Seno K, Nishizawa Y, Hayashi F, Yamazaki A, Matsumoto H, Wakabayashi T, Usukura J (1994) Ultrastructural localization of retinal guanylate cyclase in human and monkey retinas. Exp Eye Res 59:761–768Google Scholar
  40. Liu Y, Ruoho AE, Rao VD, Hurley JH (1997) Catalytic mechanism of the adenylyl and guanylyl cyclases:modeling and mutational analysis. Proc Natl Acad Sci USA 94:13414–13419Google Scholar
  41. Lopez MJ, Wong SK, Kishimoto I, Dubois S, Mach V, Friesen J, Garbers DL, Beuve A (1995) Salt-resistant hypertension in mice lacking the guanylyl cyclase-A receptor for atrial natriuretic peptide. Nature 378:65–68Google Scholar
  42. Lopez MJ, Garbers DL, Kuhn M (1997) The guanylyl cyclase-deficient mouse defines differential pathways of natriuretic peptide signaling. J Biol Chem 272:23064–23068Google Scholar
  43. Lowe DG (1992) Human natriuretic peptide receptor-A guanylyl cyclase is self-associated prior to hormone binding. Biochemistry 31:10421–10425Google Scholar
  44. Mann EA, Jump ML, Wu J, Yee E, Giannella RA (1997) Mice lacking the guanylyl cyclase C receptor are resistant to STa-induced intestinal secretion. Biochem Biophys Res Commun 239:463–466Google Scholar
  45. Nakane M, Arai K, Saheki S, Kuno T, Buechler W, Murad F (1990) Molecular cloning and expression of cDNAs coding for soluble guanylate cyclase from rat lung. J Biol Chem 265:16841–16845Google Scholar
  46. Oliver PM, Fox JE, Kim R, Rockman HA, Kim HS, Reddick RL, Pandey KN, Milgram SL, Smithies O, Maeda N (1997) Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A. Proc Natl Acad Sci USA 94:14730–14735Google Scholar
  47. Oliver PM, John SW, Purdy KE, Kim R, Maeda N, Goy MF, Smithies O (1998) Natriuretic peptide receptor 1 expression influences blood pressures of mice in a dose-dependent manner. Proc Natl Acad Sci USA 95:2547–2551Google Scholar
  48. Perrault I, Rozet JM, Calvas P, Gerber S, Camuzat A, Dollfus H, Chatelin S, Souied E, Ghazi I, Leowski C, Bonnemaison M, Le Paslier D, Frezal J, Dufier JL, Pittler S, Munnich A, Kaplan J (1996) Retinal-specific guanylate cyclase gene mutations in Leber's congenital amaurosis. Nature Genet 14:461–464Google Scholar
  49. Perrault I, Rozet JM, Gerber S, Kelsell RE, Souied E, Cabot A, Hunt DM, Munnich A, Kaplan J (1998) A retGC-1 mutation in autosomal dominant cone-rod dystrophy. Am J Hum Genet 63:651–654Google Scholar
  50. Potter LR (1998) Phosphorylation-dependent regulation of the guanylyl cyclaselinked natriuretic peptide receptor B:dephosphorylation is a mechanism of desensitization. Biochemistry 37:2422–2429Google Scholar
  51. Potter LR, Garbers DL (1992) Dephosphorylation of the guanylyl cyclase-A receptor causes desensitization. J Biol Chem 267:14531–14534Google Scholar
  52. Potter LR, Hunter T (1998) Phosphorylation of the kinase homology domain is essential for activation of the A-type natriuretic peptide receptor. Mol Cell Biol 18:2164–2172Google Scholar
  53. Schrammel A, Behrends S, Schmidt K, Koesling D, Mayer B (1996) 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 50:1–5Google Scholar
  54. Schulz S, Lopez MJ, Kuhn M, Garbers DL (1997) Disruption of the guanylyl cyclase-C gene leads to a paradoxical phenotype of viable but heat-stable enterotoxinresistant mice. J Clin Invest 100:1590–1595Google Scholar
  55. Schulz S, Wedel BJ, Matthews A, Garbers DL (1998) The cloning and expression of a new guanylyl cyclase orphan receptor. J Biol Chem 273:1032–1037Google Scholar
  56. Snyder SH (1992) Nitric oxide:First in a new class of neurotransmitters? Science 257:494–496Google Scholar
  57. Stone JR, Marletta MA (1995a) Heme stoichiometry of heterodimeric soluble guanylate cyclase. Biochemistry 34:14668–14674Google Scholar
  58. Stone JR, Marletta MA (1995b) The ferrous heme of soluble guanylate cyclase:formation of hexacoordinate complexes with carbon monoxide and nitrosomethane. Biochemistry 34:16397–16403Google Scholar
  59. Stone JR, Marletta MA (1996) Spectral and kinetic studies on the activation of soluble guanylate cyclase by nitric oxide. Biochemistry 35:1093–1099Google Scholar
  60. Stone JR, Marletta MA (1998) Synergistic activation of soluble guanylate cyclase by YC-1 and carbon monoxide:implications for the role of cleavage of the ironhistidine bond during activation by nitric oxide. Chem Biol 5:255–261Google Scholar
  61. Stults JT, O'Connell KL, Garcia C, Wong S, Engel AM, Garbers DL, Lowe DG (1994) The disulfide linkages and glycosylation sites of the human natriuretic peptide receptor-C homodimer. Biochemistry 33:11372–11381Google Scholar
  62. Sunahara RK, Beuve A, Tesmer JJ, Sprang SR, Garbers DL, Gilman AG (1998) Exchange of substrate and inhibitor specificites between adenylyl and guanylyl cyclases. J Biol Chem 273:16332–16338Google Scholar
  63. Tang WJ, Gilman AG (1995) Construction of a soluble adenylyl cyclase activated by Gs alpha and forskolin. Science 268:1769–1772Google Scholar
  64. Taylor SS, Knighton DR, Zheng J, Ten Eyck LF, Sowadski JM (1992) Structural framework for the protein kinase family. Ann Rev Cell Biol 8:429–462Google Scholar
  65. Tesmer JJ, Sunahara RK, Gilman AG, Sprang SR (1997) Crystal structure of the catalytic domains of adenylyl cyclase in a complex with Gsalpha.GTPgammaS. Science 278:1907–1916Google Scholar
  66. Thompson DK, Garbers DL (1995) Dominant negative mutations of the guanylyl cyclase-A receptor. Extracellular domain deletion and catalytic domain point mutations. J Biol Chem 270:425–430Google Scholar
  67. Thorpe DS, Morkin E (1990) The carboxyl region contains the catalytic domain of the membrane form of guanylate cyclase. J Biol Chem 265:14717–14720Google Scholar
  68. Traylor TG, Sharma VS (1992) Why NO?. Biochemistry 31:2847–2849Google Scholar
  69. Tucker CL, Hurley JH, Miller TR, Hurley JB (1998) Two amino acid substitutions convert a guanylyl cyclase, RetGC-1, into an adenylyl cyclase. Proc Natl Acad Sci USA 95:5993–5997Google Scholar
  70. Vaandrager AB, van der Wiel E, de Jonge HR (1993) Heat-stable enterotoxin activation of immunopurified guanylyl cyclase C. Modulation by adenine nucleotides. J Biol Chem 268:19598–19603Google Scholar
  71. Verma A, Hirsch DJ, Glatt CE, Ronnett GV, Snyder SH (1993) Carbon monoxide:a putative neural messenger. Science 259:381–384Google Scholar
  72. Wada A, Hasegawa M, Matsumoto K, Niidome T, Kawano Y, Hidaka Y, Padilla PI, Kurazono H, Shimonishi Y, Hirayama T (1996) The significance of Ser 1029 of the heat-stable enterotoxin receptor (STaR):relation of STa-mediated guanylyl cyclase activation and signaling by phorbol myristate acetate. FEBS Lett 384:75–77Google Scholar
  73. Wedel BJ, Garbers DL (1998) Guanylyl cyclases:approaching year thirty. Trends Endocinol Metab 9:213–219Google Scholar
  74. Wedel B, Humbert P, Harteneck C, Foerster J, Malkewitz J, Bohme E, Schultz G, Koesling D (1994) Mutation of His-105 in the beta 1 subunit yields a nitric oxideinsensitive form of soluble guanylyl cyclase. Proc Natl Acad Sci USA 91:2592–2596Google Scholar
  75. Wedel B, Harteneck C, Foerster J, Friebe A, Schultz G, Koesling D (1995) Functional domains of soluble guanylyl cyclase. J Biol Chem 270:24871–24875Google Scholar
  76. Weikel CS, Spann CL, Chambers CP, Crane JK, Linden J, Hewlett EL (1990) Phorbol esters enhance the cyclic GMP response of T84 cells to the heat-stable enterotoxin of Escherichia coli (STa). Infection and Immunity 58:1402–1407Google Scholar
  77. Yang R, Foster DC, Garbers DL, Fülle H (1995) Two membrane forms of guanylyl cyclase found in the eye. Proc Natl Acad Sci USA 92:602–606Google Scholar
  78. Yang RB, Garbers DL (1997) Two eye guanylyl cyclases are expressed in the same photoreceptor cells and form homomers in preference to heteromers. J Biol Chem 272:13738–13742Google Scholar
  79. Zhang G, Liu Y, Ruoho AE, Hurley JH (1997) Structure of the adenylyl cyclase catalytic core. Nature 386:247–253Google Scholar
  80. Zhao Y, Marletta MA (1997) Localization of the heme binding region in soluble guanylate cyclase. Biochemistry 36:15959–15964Google Scholar
  81. Zhao Y, Schelvis JPM, Babcock GT, Marletta MA (1998) Identification of histidine 105 in the β1 subunit of soluble guanylate cyclase as the heme proximal ligand. Biochemistry 37:4502–4509Google Scholar

Copyright information

© Springer-Verlag 1999

Authors and Affiliations

  • D. C. Foster
    • 1
  • B. J. Wedel
    • 1
  • S. W. Robinson
    • 1
  • D. L. Garbers
    • 1
  1. 1.Howard Hughes Medical Institute and Department of PharmacologyUniversity of Texas Southwestern Medical CenterDallas

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