Tetanus Toxin Inhibits a Membrane Guanylate Cyclase Transduction System

  • Alexander A. Fedinec
  • Teresa Duda
  • Bernard Bizzini
  • Nigel G. F. Cooper
  • Rameshwar K. Sharma


Original studies suggested that tetanus toxin (TT) in vivo exerts its paralytic effect on cholinergic nerve terminals in rabbit iris by interfering with cyclic GMP pathway (Fedinec, et al. 1976 and King, et al. 1978). One possible target site of TT for this effect is guanylate cyclase, the enzyme that catalyzes the formation of cyclic GMP. There are two forms of guanylate cyclases—soluble and membrane bound. Thus, if TT exerts its paralytic activity through the interference with guanylate cyclase activity, then the toxin could cause such interference by acting on soluble or membrane bound guanylate cyclase. In this study we have considered the latter possibility. Specifically, using the combined tools of immunology and genetically-tailored mutants, we have studied the effect of TT directly on the basal activity of plasma membrane guanylate cyclase, GCα (Duda et al., 1991), and on the ANF-dependent cyclase activity of the genetically-constructed ANF receptor guanylate cyclases, GCα-DmutGln338Leu364 and GCα-SmutLeu364.


Brain Natriuretic Peptide Guanylate Cyclase Atrial Natriuretic Factor Botulinum Neurotoxin Tetanus Toxin 
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.


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  1. Aleksevich YI. Peculiarities of oxidative metabolism in tetanus. In: Nistico G, Bizzini B, Bytchenko BGoogle Scholar
  2. Triau R, eds. Eighth International Conference on Tetanus. Rome: Pythagora Press, 1989: 34.Google Scholar
  3. Bizzini B, Turpin A, Raynaud M. Production et purification de la toxine tetanique. Ann Inst Pasteur 1968; 101: 1212.Google Scholar
  4. Bizzini B. Axoplasmic transport and transsynaptic movement of tetanus toxin. In: Simpson LL, ed. Botulinum neurotoxin and tetanus toxin. New York: Academic Press, Inc., 1989: 203.CrossRefGoogle Scholar
  5. Bizzini B, Fedinec AA. Structural and functional characterization of tetanus toxin. In: Nistico G, Bizzini B, Bytchenko B, Triau R, eds. Eighth International Conference on Tetanus. Rome: Pythagora Press, 1989: 37.Google Scholar
  6. Chang MS, Lowe DG, Lewis M, Hellmis R, Chen E, Goeddel DV. Differential activation by atrial and brain natriuretic peptides of two different guanylate cyclases. Nature 1989; 341: 68.PubMedCrossRefGoogle Scholar
  7. Chinkers M, Garben DL, Chang MS, Lowe DG, Goeddel DV, Schultz S. A membrane form of guanylate cyclase is an atrial natriuretic peptide receptor. Nature 1989; 338: 78.PubMedCrossRefGoogle Scholar
  8. Cooper NGF, McLaughlin BJ, Tallant EA, Cheung WY. Calmodulin-dependent protein phosphatase: Immunocytochemical localization in Chick retina. J Cell Biol 1985; 101: 1212.PubMedCrossRefGoogle Scholar
  9. Cooper NGF, Fedinec AA, Sharma RK. Immunocytochemistry of the 180-kDa membrane guanylate cyclase in the retina. ARVO Supplement to Investigative Ophthalmology and Visual Science 1989; 30: 295.Google Scholar
  10. Cooper NGF, Fedinec AA, Sharma RK. ANF-receptor coupled guanylate cyclase in CNS synapses. Soc Neurosci 1990, 16: 537.Google Scholar
  11. Dastur FD. Tetanus-pathophysiology as a guide to treatment. In: Nistico G, Bizzini B, Bytchenko B, Triau R, eds. Eighth International Conference on Tetanus, Rome: Pythagora Press, 1989: 630.Google Scholar
  12. Dryer F. Peripheral actions of tetanus toxin. In: Simpson LL, ed. Botulinum neurotoxin and tetanus toxin, London: Academic Press, 1989: 179.Google Scholar
  13. Duda T, Goraczniak RM, Sharma RK. Site-directed mutational analysis of a membrane guanylate cyclase cDNA reveals the atrial natriuretic factor signaling site. Proc Natl Acad Sci USA 1991; 88: 7882.PubMedCrossRefGoogle Scholar
  14. Fedinec AA, King LE Jr, Latham WC. Glycine, theophilline and antitoxin effects on rabbit sphincter pupillae muscle paralyzed by tetanus toxin. In: Ohaska A, Hayashi K, Sawai Y, eds. Animal, Plant and Microbial Toxins. New York: Plenum Publ. Corp., 1976; 2: 351.CrossRefGoogle Scholar
  15. Fedinec AA, Cooper NGF, Sharma RK. Immunocytochemical localization of the 180-kDa guanylate cyclase in the rat brain. Soc Neurosci 1988; 14:(1)363.Google Scholar
  16. Fedinec AA, Duda T, Cooper NGF, Sharma RK, Bizzini B Inhibition of ANF-dependent 180-kDa membrane guanylate cyclase by tetanus toxin: a potential mechanism of action. Toxicon 1989; 27: 44.Google Scholar
  17. Flynn TGB, Anoop B, Tremblay L, Sarda I. Isolation and characterization of ISO-rANP, a new natriuretic peptide from rat atria. Biochem Biophys Res Commun 1989; 161: 830.PubMedCrossRefGoogle Scholar
  18. Goraczniak RM, Duda T, Sharma RK. A structural motif that defines the ATP-regulatory module of guanylate cyclase in atrial natriuretic factor signalling. Biochem. J 1992; 282: 533.PubMedGoogle Scholar
  19. Habermann E. Clostridial neurotoxins and the central nervous system: Functional studies on isolated preparations. In: Simpson LL, ed. Botulinum neurotoxin and tetanus toxin. London: Academic Press, 1989, 255.Google Scholar
  20. Hashiguchi T, Higuchi K, Ohask M, Minamino N, Kangawa K, Matsuo H, Nawata H. Porcine brain natriuretic peptide, another modulator of bovine adrenocortical steroidogenesis. FEBS Lett 1988; 236: 455.PubMedCrossRefGoogle Scholar
  21. King LE Jr, Fedinec AA, Latham WC. Effects of cyclic nucleotides on tetanus toxin paralyzed rabbit sphincter pupillae muscle. Toxicon 1978; 16: 625.PubMedCrossRefGoogle Scholar
  22. Kryzhanovsky GN. Pathophysiology. In: Veronesi R, ed. Tetanus. Important new concepts. CasparieAmsterdam: Excerpta Medica, 1981: 109.Google Scholar
  23. Kuno T, Anderson W, Kamisaka Y, Waldman SA, Chang LY, Saheki S, Leitman DC, Nakane M, Murad F. Copurification of an atrial natriuretic factor receptor and particulate guanylate cyclase. J Biol Chem 1986; 261: 5817.PubMedGoogle Scholar
  24. Marala RB, Sharma RK. Ubiquitous and bifunctional 180 kDa atrial natriuretic factor-dependent guanylate cyclase. Mol Cell Biochem 1991; 100: 25.PubMedCrossRefGoogle Scholar
  25. Marala R, Duda T, Goraczniak RM, Sharma RK. Genetically tailored atrial natriuretic factor-dependent guanylate cyclase. Immunological and functional identity with 180 kDa membrane guanylate cyclase and ATP signaling site. FEBS Lett 1992; 296 (3): 254.PubMedCrossRefGoogle Scholar
  26. Meloche S, McNocoll N, Liu B, Ong H, DeLean AD. Atrial natriuretic factor R 1 receptor from bovine adrenal zona glomerulosa: purification, characterization, and modulation by amiloride. Biochemistry 1988; 27: 8151.PubMedCrossRefGoogle Scholar
  27. Nambi P, Aiyar NV, Roberts AN, Sharma RK. Relationship of calcium and membrane guanylate cyclase in adrenocorticotropin-induced steroidogenesis. Endocrinology 1982; 111: 196.PubMedCrossRefGoogle Scholar
  28. Paul AK, Marala RB, Jaiswal RK, Sharma RK. Co-existence of guanylate cyclase and atrial natriuretic factor receptor in a 180 kD protein. Science 1987; 235: 1224.PubMedCrossRefGoogle Scholar
  29. Rosenzweig A, Seidman CE. Atrial natriuretic factor related peptide hormones. Annu Rev Biochem 1991; 60: 229.PubMedCrossRefGoogle Scholar
  30. Sharma RK, Marala RB, Duda T. Purification and characterization of the 180-kDa membrane guanylate cyclase containing atrial natriuretic factor receptor from adrenal gland and its regulation by protein kinase C. Steroids 1989; 53: 437.PubMedCrossRefGoogle Scholar
  31. Sudoh T, Kangawa K, Minamino N, Matsuo H. A new natriuretic peptide in porcine brain. Nature (London) 1988; 332: 78.CrossRefGoogle Scholar
  32. Takayanagi KS, Snajdan RM, Imada T, Timura M, Pandey L, Misono KS, Inagami T. Purification and characterization of two types of atrial natriuretic factor receptors from bovine adrenal cortex: Guanylate cyclase-linked and cyclase free receptors. Biochem Biophys Res Commun 1987; 144: 244.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • Alexander A. Fedinec
    • 1
  • Teresa Duda
    • 2
  • Bernard Bizzini
    • 3
  • Nigel G. F. Cooper
    • 4
  • Rameshwar K. Sharma
    • 2
  1. 1.Department of Anatomy and NeurobiologyThe University of TennesseeMemphisUSA
  2. 2.Unit of Regulatory and Molecular BiologyPennsylvania College of OptometryPhiladelphiaUSA
  3. 3.Department of Molecular ToxicologyInstitute PasteurParisFrance
  4. 4.Department of Anatomical Sciences and Neurobiology, School of MedicineUniversity of LouisvilleUSA

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