Molecular Neurobiology

, Volume 29, Issue 2, pp 97–115 | Cite as

Invertebrates yield a plethora of atypical guanylyl cyclases

  • 1David B. Morton


Invertebrate model systems have a long history of generating new insights into neuronal signaling systems. This review focuses on cyclic GMP signaling and describes recent advances in understanding the properties and functions of guanylyl cyclases in invertebrates. The sequencing of three invertebrate genomes has provided a complete catalog of the guanylyl cyclases in C. elegans, Drosophila, and the mosquito Anopheles gambiae. Using this data and that from cloned guanylyl cyclases in Manduca sexta, C. elegans, and Drosophila, plus predictions and models from vertebrate guanylyl cyclases, evidence is presented that there is a much broader array of properties for these enzymes than previously realized. In addition to the classic homodimeric receptor guanylyl cyclases, C. elegans has at least two receptor guanylyl cyclases that are predicted to require heterodimer formation for activity. Soluble guanylyl cyclases are generally recognized as being obligate heterodimers that are activated by nitric oxide (NO). Some of the soluble guanylyl cyclases in C. elegans may heterodimeric, but all appear to be insensitive to NO. The β2 soluble guanylyl cyclase subunit in mammals and similar ones in Manduca and Drosophila are active in the absence of additional subunits and there is evidence that Drosophila and Anopheles also express an additional subunit that enhances this activity.

Index Entries

Cyclic GMP guanylyl cyclase nitric oxide signal transduction 


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  1. 1.
    Lucas K. A., Pitari G. M., Kazerounian S., Ruiz-Stewart I., Park J., Schulz S., Chepenik K. P., and Waldman S. A. (2000). Guanylyl cyclases and signaling by cyclic GMP. Pharmacol. Rev. 52, 375–413.PubMedGoogle Scholar
  2. 2.
    Morton D. B. and Truman J. W. (1985). Steroid regulation of the peptide-mediated increase in cyclic GMP in the nervous system of the hawkmoth, Manduca sexta. J. Comp. Physiol. 157, 423–432.CrossRefGoogle Scholar
  3. 3.
    Osborne K. A., Robichon A., Burgess E., et al. (1997). Natural behavior polymorphism due to a cGMP-dependent protein kinase of Drosophila. Science 277, 834–836.PubMedCrossRefGoogle Scholar
  4. 4.
    L’Etoile N. D. and Bargmann C. I. (2000). Olfaction and odor discrimination are mediated by the C. elegans guanylyl cyclase ODR-1. Neuron 25, 575–586.PubMedCrossRefGoogle Scholar
  5. 5.
    Wright J. W., Schwinof K. M., Snyder M. A., and Copenhaver P. F. (1998). A delayed role for nitric oxide-sensitive guanylate cyclases in a migratory population of embryonic neurons. Dev. Biol. 204, 15–33.PubMedCrossRefGoogle Scholar
  6. 6.
    Gibbs S. M. and Truman J. W. (1998). Nitric oxide and cyclic GMP regulate retinal patterning in the optic lobe of Drosophila. Neuron 20, 83–93.PubMedCrossRefGoogle Scholar
  7. 7.
    Van Wagenen S. and Rehder V. (2001). Regulation of neuronal growth cone filopodia by nitric oxide depends on soluble guanylyl cyclase. J. Neurobiol. 46, 206–219.PubMedCrossRefGoogle Scholar
  8. 8.
    Singh S., Lowe D. G., Thorpe D. S., et al. (1988). Membrane guanylate cyclase is a cell-surface receptor with homology to protein kinases. Nature 334, 708–712.PubMedCrossRefGoogle Scholar
  9. 9.
    Liu W., Moon J., Burg M., Chen L., and Pak W. L. (1995). Molecular characterization of two Drosophila guanylate cyclases expressed in the nervous system. J. Biol. Chem. 270, 12,418–12,427.Google Scholar
  10. 9.
    Gigliotti S., Cavaliere V., Manzi A., Tino A., Graziani F., and Malva C. (1993). A membrane guanylate cyclase Drosophila homologue gene exhibits maternal and zygotic expression. Dev. Biol. 159, 450–461.PubMedCrossRefGoogle Scholar
  11. 11.
    McNeil L., Chinkers M., and Forte M. (1995). Identification, characterization and developmental regulation of a receptor guanylyl cyclase expressed during early stages of Drosophila development. J. Biol. Chem. 270, 7189–7196.PubMedCrossRefGoogle Scholar
  12. 12.
    Tanoue S., Sumida S., Suetsugu T., Endo Y., and Nishioka T. (2001). Identification of a receptor type guanylyl cyclase in the antennal lobe and antennal sensory neurons of the silkmoth, Bombyx mori. Insect Biochem. Mol. Biol. 31, 971–979.PubMedCrossRefGoogle Scholar
  13. 13.
    Tanoue S. and Nishioka T. (2001). A receptor-type guanylyl cyclase expression is regulated under circadian clock in peripheral tissues of the silk moth. Light-induced shifting of the expression rhythm and correlation with eclosion. J. Biol. Chem. 276, 46,765–46,769.Google Scholar
  14. 14.
    Morton D. B. and Nighorn A. (2003). MsGC-II, a receptor guanylyl cyclase isolated from the CNS of Manduca sexta that is inhibited by calcium. J. Neurochem. 84, 363–372.PubMedCrossRefGoogle Scholar
  15. 15.
    Morton D. B. and Hudson M. L. (2002). Cyclic GMP regulation and function in insects. Adv. Insect Physiol. 29, 1–54.CrossRefGoogle Scholar
  16. 16.
    Kuryatov A., Laube B., Betz H., and Kuhse J. (1994). Mutational analysis of the glycine-binding site of the NMDA receptor: structural similarity with bacterial amino acid-binding proteins. Neuron 12, 1291–1300.PubMedCrossRefGoogle Scholar
  17. 17.
    Goy M. F. (1990). Activation of membrane guanylate cyclase by an invertebrate peptide hormone. J. Biol. Chem. 265, 20,220–20,227.Google Scholar
  18. 18.
    Scholz N. L., Goy M. F., Truman J. W., and Graubard K. (1996). Nitric oxide and peptide neurohormones activate cGMP synthesis in the crab stomatogastric nervous system. J. Neuroscience 16, 1614–1622.Google Scholar
  19. 19.
    Birnby D. A., Link E. M., Vowels J. J., Tian H., Colacurcio P. L., and Thomas J. H. (2000). A transmembrane guanylyl cyclase (DAF-11) and Hsp90 (DAF-21) regulate a common set of chemosensory behaviors in Caenorhabditis elegans. Genetics 155, 85–104.PubMedGoogle Scholar
  20. 20.
    Shah S. and Hyde D. R. (1995). Two Drosophila genes that encode the α and β subunits of the brain soluble guanylyl cyclase. J. Biol. Chem. 270, 15,368–15,376.CrossRefGoogle Scholar
  21. 21.
    Nighorn A., Gibson N. J., Rivers D. M., Hildebrand J. G., and Morton D. B. (1998). The NO/cGMP pathway may mediate communication between sensory afferents and projection neurons in the antennal lobe of Manduca sexta. J. Neurosci. 18, 7244–7255.PubMedGoogle Scholar
  22. 22.
    Caccone A., Garcia B. A., Mathiopoulos K. D., Min G. S., Moriyama E. N., and Powell J. R. (1999). Characterization of the soluble guanylyl cyclase beta-subunit gene in the mosquito Anopheles gambiae. Insect Mol. Biol. 8, 23–30.PubMedCrossRefGoogle Scholar
  23. 23.
    Holt R. A., Subramanian G. M., Halpern A., et al. (2002). The Genome sequence of the malaria mosquito Anopheles gambiae. Science 298, 129–149.PubMedCrossRefGoogle Scholar
  24. 24.
    Gibson N. J. and Nighorn A. (2000). Expression of nitric oxide synthase and soluble guanylyl cyclase in the developing olfactory system of Manduca sexta. J. Comp. Neurol. 422, 191–205.PubMedCrossRefGoogle Scholar
  25. 25.
    Zayas R. M., Qazi S., Morton D. B., and Trimmer B. A. (2000). Neurons involved in nitric oxide mediated cGMP signaling in the tobacco hornworm, Manduca sexta. J. Comp Neurol. 419, 422–438.PubMedCrossRefGoogle Scholar
  26. 26.
    Wildman B. and Bicker G. (1999). Developmental expression of nitric oxide/cyclic GMP synthesizing cells in the nervous system of Drosophila melanogaster. J. Neurobiol. 38, 1–15.CrossRefGoogle Scholar
  27. 27.
    Scholz N. L., Chang E. S., Graubard K., and Truman J. W. (1998). The NO/cGMP pathway and the development of neural networks in postembryonic lobsters. J. Neurobiol. 34, 208–226.PubMedCrossRefGoogle Scholar
  28. 28.
    Huang S., Kerschbaum H. H., and Hermann A. (1998). Nitric oxide-mediated cGMP synthesis in Helix neural ganglia. Brain. Res. 780, 329–336.PubMedCrossRefGoogle Scholar
  29. 29.
    Nighorn A., Byrnes K. A., and Morton D. B. (1999). Identification and characterization of a novel beta subunit of soluble guanylyl cyclase that is active in the absence of additional subunits and relatively insensitive to nitric oxide. J. Biol. Chem. 274, 2525–2531.PubMedCrossRefGoogle Scholar
  30. 30.
    Truman J. W., De Vente J., and Ball E. E. (1996). Nitric oxide-sensitive guanylate cyclase activity is associated with the maturational phase of neuronal development in insects. Development 122, 3949–3958.PubMedGoogle Scholar
  31. 31.
    Ball E. E. and Truman J. W. (1998). Developing grasshopper neurons show variable levels of guanylyl cyclase activity on arrival at their targets. J. Comp. Neurol. 394, 1–13.PubMedCrossRefGoogle Scholar
  32. 32.
    Gibbs S. M., Becker A., Hardy R. W., and Truman J. W. (2001). Soluble guanylate cyclase is required during development for visual system function in Drosophila. J. Neurosci. 21, 7705–7714.PubMedGoogle Scholar
  33. 33.
    Seidel C. and Bicker G. (2000). Nitric oxide and cGMP influence axonogenesis of antennal pioneer neurons. Development 127, 4541–4549.PubMedGoogle Scholar
  34. 34.
    Bicker G. (2001). Sources and targets of nitric oxide signalling in insect nervous systems. Cell Tissue Res. 303, 137–146.PubMedCrossRefGoogle Scholar
  35. 35.
    Davies S. A. (2000). Nitric oxide signalling in insects. Insect Biochem. Mol. Biol. 30, 1123–1138.PubMedCrossRefGoogle Scholar
  36. 36.
    Bargmann C. I. (1998). Neurobiology of the Caenorhabditis elegans genome. Science 282, 2028–2033.PubMedCrossRefGoogle Scholar
  37. 37.
    Yu S., Avery L., Baude E., and Garbers D. L. (1997). Guanylyl cyclase expression in specific sensory neurons: A new family of chemosensory receptors. Proc. Natl. Acad. Sci. USA 94, 3384–3387.PubMedCrossRefGoogle Scholar
  38. 38.
    Colbert H. A. and Bargmann C. I. (1995). Odorant-specific adaptation pathways generate olfactory plasticity in C. elegans. Neuron 14, 803–812.PubMedCrossRefGoogle Scholar
  39. 39.
    Riddle D. L. and Albert P. S. (1997). Genetic and environmental regulation of dauer larva development: In C. elegans II, Riddle D. L., Blumenthal T., Meyer J., and Priess J. R., eds., Cold Spring Harbor Press, Plainview, NY, pp. 739–768.Google Scholar
  40. 40.
    Liu Y., Ruoho A. E., Rao V. D., and Hurley J. H. (1997). Catalytic mechanism of the adenylyl and guanylyl cyclases: modeling and mutational analysis. Proc. Natl. Acad. Sci. USA 94, 13,414–13,419.Google Scholar
  41. 41.
    Tucker C. L., Hurley J. H., Miller T. R., and Hurley J. B. (1998). Two amino acid substitutions convert a guanylyl cyclase, RetGC-1, into an adenylyl cyclase. Proc. Natl. Acad. Sci. USA 95, 5993–5997.PubMedCrossRefGoogle Scholar
  42. 42.
    Simpson P. J., Nighorn A., and Morton D. B. (1999). Identification and characterization of a novel guanylyl cyclase that is related to receptor guanylyl cyclases, but lacks extracellular and transmembrane domains. J. Biol. Chem. 274, 4440–4446.PubMedCrossRefGoogle Scholar
  43. 43.
    Nighorn A., Simpson P. J., and Morton D. B. (2001). The novel guanylyl cyclase MsGC-I is strongly expressed in higher order neuropils in the brain of Manduca sexta. J. Exp. Biol. 204, 305–314.PubMedGoogle Scholar
  44. 44.
    Grueber W. B. and Truman J. W. (1999). Development and organization of a nitric oxide-sensitive peripheral neural plexus in larvae of the moth, Manduca sexta. J. Comp. Neurol. 404, 127–141.PubMedCrossRefGoogle Scholar
  45. 45.
    Grueber W. B. Nighorn A., Morton D. B., and Truman J. W. (2001). Co-localization of the guanylyl cyclase MsGC-I and frequenin suggests a mechanism for EGTA-stimulated cGMP production in sensory neurons. Soc. Neurosci. Abs. 27.Google Scholar
  46. 46.
    Kojima M., Hisaki K., Matsuo H., and Kangawa K. (1995). A new type of soluble guanylyl cyclase, which contains a kinase-like domain—its structure and expression. Biochem. Biophys. Res. Comm. 217, 993–1000.PubMedCrossRefGoogle Scholar
  47. 47.
    Schulz S., Wedel B. J., Matthews A., and Garbers D. L. (1998). The cloning and expression of a new guanylyl cyclase orphan receptor. J. Biol. Chem. 273, 1032–1037.PubMedCrossRefGoogle Scholar
  48. 48.
    Friebe A., Wedel B., Harteneck C., Foerster J., Schultz G., and Koesling D. (1997). Functions of conserved cysteines of soluble guanylyl cyclases. Biochemistry 36, 1194–1198.PubMedCrossRefGoogle Scholar
  49. 49.
    Morton D. B. and Anderson E. (2003). MsGC-β3 forms active homodimers and inactive heterodimers with NO-sensitive soluble guanylyl cyclase subunits. J. Exp. Biol. 206, 937–947.PubMedCrossRefGoogle Scholar
  50. 50.
    Zabel U., Häusler C., Weeger M., and Schmidt H. W. (1999). Homodimerization of soluble guanylyl cyclase subunits: dimerization analysis using glutathione S-transferase affinity tag. J. Biol. Chem. 274, 18,149–18,152.CrossRefGoogle Scholar
  51. 51.
    Ewer J. and Reynolds S. (2002). Neuropeptide control of molting in insects. Hormones, Brain and Behavior 3, 1–92.Google Scholar
  52. 48.
    Mesce K. A. and Fahrbach S. E. (2002). Integration of endocrine signals that regulate insect ecdysis. Frontiers in Neuroendocrinology 23, 179–199.PubMedCrossRefGoogle Scholar
  53. 53.
    Truman J. W., Mumby S. M., and Welch S. K. (1979). Involvement of cyclic GMP in the release of stereotyped behavior patterns in moths by a peptide hormone. J. Exp. Biol. 84, 201–212.Google Scholar
  54. 54.
    Morton D. B. and Simpson P. J. (2002). Cellular signaling in eclosion hormone action. J. Insect Physiol. 48, 1–13.PubMedCrossRefGoogle Scholar
  55. 55.
    Ewer J., De Vente J., and Truman J. W. (1994). Neuropeptide induction of cyclic GMP increase in the insect CNS: resolution at the level of single identifiable neurons. J. Neurosci. 14, 7704–7712.PubMedGoogle Scholar
  56. 56.
    Kingan T. G., Gray W., Zitnan D., and Adams M. E. (1997). Regulation of ecdysis-triggering hormone release by eclosion hormone. J. Exp. Biol. 200, 3245–3256.PubMedGoogle Scholar
  57. 57.
    Kingan T. G., Cardullo R. A., and Adams M. E. (2001). Signal transduction in eclosion hormone-induced secretion of ecdysis-triggering hormone. J. Biol. Chem. 276, 25,136–25,142.CrossRefGoogle Scholar
  58. 58.
    Hesterlee S. and Morton D. B. (2000). Identification of the cellular target for eclosion hormone in the abdominal transverse nerves of the tobacco hornworm, Manduca sexta. J. Comp. Neurol. 424, 339–355.PubMedCrossRefGoogle Scholar
  59. 59.
    Morton D. B. (2000). Localization of the NO-insensitive soluble guanylyl cyclase, MsGC-β3, to the abdominal transverse nerves of Manduca suggests a role in eclosion hormone action. Soc. Neurosci. Abstracts 26.Google Scholar
  60. 60.
    Yuen P. S. T., Potter L. R., and Garbers D. L. (1990). A new form of guanylyl cyclase is preferentially expressed in rat kidney. Biochem. 29, 10,872–10,878.Google Scholar
  61. 61.
    Gupta G., Azam M., Yang L., and Danziger R. S. (1997). 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.PubMedCrossRefGoogle Scholar
  62. 62.
    Koglin M., Vehse K., Budaeus L., Scholz H., and Behrends S. (2001). Nitric oxide activates the β2 subunit of soluble guanylyl cyclase in the absence of a second subunit. J. Biol. Chem. 276, 30,737–30,743.CrossRefGoogle Scholar
  63. 63.
    Morton D. B., Hudson M. L., Waters E., and O’Shea M. (1999). Soluble guanylyl cyclases in C. elegans—NO si not the answer. Current Biology 9, R546–547.PubMedCrossRefGoogle Scholar
  64. 64.
    Hudson M. L., Karow D. S., Marletta M. A., and Morton D. B. (2000). Characterization of the soluble guanylyl cyclase gene family in Caenorhabditis elegans. Soc. Neurosci. Abstracts 26.Google Scholar
  65. 65.
    de Bono M. and Bargmann C. I. (1998). A natural variation in a neuropeptide Y homolog modifies social behavior and feeding response in C. elegans. Cell 94, 679–689.PubMedCrossRefGoogle Scholar
  66. 66.
    Coates J. C. and de Bono M. (2002). Antagonistic pathways in neurons exposed to body fluid regulate social feeding in Caenorhabditis elegans. Nature 419, 925–929.PubMedCrossRefGoogle Scholar
  67. 67.
    de Bono M., Tobin D. M., Davis M. W., Avery L., and Bargmann C. I. (2002). Social feeding in Caenorhabditis elegans is induced by neurons that detect aversive stimuli. Nature 419, 899–903.PubMedCrossRefGoogle Scholar
  68. 68.
    Sokolowski M. B. (1998). Genes for normal behavioral variation: Recent clues from worms and flies. Neuron 21, 463–466.PubMedCrossRefGoogle Scholar
  69. 69.
    Sokolowski M. B. (1980). Foraging strategies of Drosophila melanogaster: a chromosomal analysis. Behavior Genetics. 10, 291–302.PubMedCrossRefGoogle Scholar
  70. 70.
    Morton D. B., Stewart J. A., and Langlais K. K. (2003). Preliminary characterization of two atypical soluble guanylyl cyclases from Drosophila. Soc. Neurosci. Abs. 29.Google Scholar

Copyright information

© Humana Press Inc 2004

Authors and Affiliations

  • 1David B. Morton
    • 1
  1. 1.Department of Integrative BiosciencesOregon Health and Science UniversityPortland

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