Role of Neuronal Ion Channels in Mercury Intoxication

  • Toshio Narahashi
  • Osamu Arakawa
  • Masanobu Nakahiro
Part of the Rochester Series on Environmental Toxicity book series (RSET)


Mercury compounds exert multiple actions on the nervous system. At skeletal neuromuscular junctions, mercury increases spontaneous release of acetylcholine from nerve terminals and suppresses the nerve-evoked synchronized release of acetylcholine. Voltage-activated sodium and potassium channels of neuronal membranes are suppressed by mercury causing conduction block. Our recent patch clamp study with the rat dorsal root ganglion neurons has unveiled a highly potent and efficacious action of mercuric chloride in augmenting the GABA-activated chloride channel current, a prominent effect being observed at 1 μM. Mercuric chloride also induced a slow inward current by itself, which is likely to account for an increase in leakage current, resting membrane conductance, and membrane depolarization. It was concluded that the stimulation of GABA-induced chloride current plays an important role in mercury intoxication.


Mercuric Chloride Mercury Compound Squid Giant Axon Methylmercuric Chloride Methylmercury Poisoning 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abdallah, E. A. M. and Shamoo, A. E., 1984. Protective effect of dimercaptosuccinic acid on methylmercury and mercuric chloride inhibition of rat brain muscarinic acetylcholine receptors. Pesticide Biochem. Physiol. 21:385–393.CrossRefGoogle Scholar
  2. Abd-Elfattah, A. S. A., and Shamoo, A. E., 1981, Regeneration of a functionally active rat brain muscarinic receptor by d-penicillamine after inhibition with methylmercury and mercuric chloride. Evidence for essential sulfhydryl groups in muscarinic receptor binding sites, Mol. Pharmacol., 20:492–497.PubMedGoogle Scholar
  3. Arakawa, O., Nakahiro, M., and Narahashi, T., 1991, Mercury modulation of GABA-activated chloride channels and non-specific cation channels in rat dorsal root ganglion neurons, Brain Res. 551:58–63.PubMedCrossRefGoogle Scholar
  4. Atchison, W. D., 1986, Extracellular calcium-dependent and-independent effects of methylmercury on spontaneous and potassium-evoked release of acetylcholine at the neuromuscular junction, J. Pharmacol. Exp. Ther., 237:672–680.PubMedGoogle Scholar
  5. Atchison, W.D., 1987, Effects of activation of sodium and calcium entry on spontaneous release of acetylcholine induced by methylmercury, J. Pharmacol. Exp. Then, 241:131–139.Google Scholar
  6. Atchison, W. D., and Narahashi, T., 1982, Methylmercury-induced depression of neuromuscular transmission in the rat, NeuroToxicoloty, 3:37–50.Google Scholar
  7. Bakir, R., Damluji, S. F., Amin-Zaki, L., Murtadha, M., Khalidi, A., Al-Rawi, N. Y., Tikriti, S., Dhahir, H. I., Clarkson, T. W., Smith, J. C., and Doherty, R. A., 1973, Methylmercury poisoning in Iraq, Science, 181:230–240.PubMedCrossRefGoogle Scholar
  8. Barker, J. L., and Ransom, B. R., 1978, Pentobarbitone pharmacology of mammalian central neurones grown in tissue culture, J. Physiol. (London), 280:355–372.Google Scholar
  9. Barrett, J., Botz, D., and Chang, D.B., 1974, Block of neuromuscular transmission by methylmercury, in: “Behavioral Toxicology, Early Detection of Occupational Hazards,” C. Xintaras, B. L. Johnson and I. de Groot, eds., Vol. 5, 277–287, U.S. Dept. of Health, Education and Welfare, Washington.Google Scholar
  10. Berlin, M., Carlson, J., and Norseth, T., 1975, Dose-dependence of methylmercury metabolism, Arch. Environ. Health, 30:307–317.PubMedCrossRefGoogle Scholar
  11. Bondy, S. C., and Agrawal, A. K., 1980, The inhibition of cerebral high affinity receptor sites by lead and mercury compounds, Arch. Toxicol., 46:249–256.PubMedCrossRefGoogle Scholar
  12. Bormann, J., and Clapham, D. E., 1985, γ-Aminobutyric acid receptor channels in adrenal chromaffin cells: A patch-clamps study, Proc. Natl. Acad. Sci. USA, 82:2168–2172.PubMedCrossRefGoogle Scholar
  13. Brown, D. A., and Constanti, A., 1978, Interaction of pentobarbitone and γ-aminobutyric acid on mammalian sympathetic ganglion cells, Brit. J. Pharmacol., 63:217–224.CrossRefGoogle Scholar
  14. Cavanaugh, J. B., and Chen, F. C. K., 1971, The effects of methyl-mercury-dicyandiamide on the peripheral nerves and spinal cord of rats, Acta Neuropathol., 19:208–215.CrossRefGoogle Scholar
  15. Chan, C. Y., and Farb, D. H. 1985, Modulation of neurotransmitter action: Control of the γ-aminobutyric acid response through the benzodiazepine receptor, J. Neuroscience, 5:2365–2373.Google Scholar
  16. Chang, L. W., 1977, Neurotoxic effects of mercury—a review, Environ. Res., 14:329–373.PubMedCrossRefGoogle Scholar
  17. Chang, L. W., 1980, Mercury in: “Environmental and Clinical Neurotoxicology,” P.S. Spencer and H. H. Schaumburg, eds., 508–526, The Williams and Wilkins, Baltimore.Google Scholar
  18. Chang, L. W., and Hartmann, H. A., 1972, Ultrastructural studies of the nervous system after mercury intoxication. II. Pathological changes in the nerve fibers, Acta Neuropathol., 20:316–331.PubMedCrossRefGoogle Scholar
  19. Choi, D. W., Farb, D. H., and Fischbach, G. D., 1981, Chlordiazepoxide selectively potentiates GABA conductance of spinal cord and sensory neurons in cell culture, J. Neurophysiol., 45:621–631.PubMedGoogle Scholar
  20. Cooper, G. P., and Manalis, R. S. 1983, Influence of heavy metals on synaptic transmission, NeuroToxicology, 4:69–84.PubMedGoogle Scholar
  21. Cooper, G. P., Suszkiw, J. B., and Manalis, R. S., 1984, Heavy metals: Effects on synaptic transmission, NeuroToxicology, 5:247–266.PubMedGoogle Scholar
  22. Eldefrawi, M. E., Monsour, N. A., and Eldefrawi, A. T., 1977, Interactions of acetylcholine receptors with organic mercury compounds, in: “Membrane Toxicity,” M.W. Miller and A.E. Shamoo, eds., 449–463, Plenum, New York.CrossRefGoogle Scholar
  23. Fehling, C., Abdulla, M., Brun, A., Dictor, M., Schütz, A., and Skerfving, S., 1975, Methylmercury poisoning in the rat: A combined neurological, chemical and histopathological study, Toxicol. Appl. Pharmacol., 33:27–37.PubMedCrossRefGoogle Scholar
  24. Hamill, O. P., Marty, A., Neher, E., Sakmann, B., and Sigworth, F. J., 1981, Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches, Pflügers Arch., 391:85–100.PubMedCrossRefGoogle Scholar
  25. Herman, S. P., Klein, R., Talley, F. A., and Krigman, M. R., 1973, An ultrastructural study of methylmercury-induced primary sensory neuropathy in the rat, Lab. Invest., 28:104–118.PubMedGoogle Scholar
  26. Hift, H., and Schultz, R., 1976, Methylmercury induced injury of single barnacle muscle fibers, Environmental Res., 11:367–385.CrossRefGoogle Scholar
  27. Hughes, W. L., 1957, A physicochemical rationale for the biological activity of mercury and its compounds, Ann. New York Acad. Sci., 65:454–460.CrossRefGoogle Scholar
  28. Hunter, D., Bomford, R., and Russell, D. S., 1940, Poisoning by methylmercury compounds, Quart. J. Med., 9:193–241.Google Scholar
  29. Jacobs, J. M., Carmichael, N., and Cavanaugh, J. B., 1975, Ultrastructural changes in the dorsal root and trigeminal ganglia of rats poisoned with methylmercury, Neuropathol. Appl. Neurobiol., 1:1–9.CrossRefGoogle Scholar
  30. Juang, M. S., 1976, An electrophysiological study of the action of methylmercuric chloride and mercuric chloride on the sciatic nerve-sartorius muscle preparation of the frog, Toxicol. Appl. Pharmacol., 37:339–348.PubMedCrossRefGoogle Scholar
  31. Juang, M. S., and Yonemura, K., 1975, Increased spontaneous transmitter release from presynaptic nerve terminal by methylmercuric chloride, Nature (London), 256:211–213.CrossRefGoogle Scholar
  32. Kato, E., Anwyl, R., Quandt, F. N., and Narahashi, T., 1983, Acetylcholine-induced electrical responses in neuroblastoma cells, Neuroscience, 8:643–651.PubMedCrossRefGoogle Scholar
  33. Le Quesne, P. M., Damaluji, S. F., and Rustam, H., 1974, Electrophysiological studies of peripheral nerves in patients with organic mercury poisoning, J. Neurol. Neurosurg. Psychol., 37:333–338.CrossRefGoogle Scholar
  34. Levesque, P. C., and Atchison, W. D., 1987, Interactions of mitochondrial inhibitors with methyl mercury on spontaneous quantal release of acetycholine, Toxicol. Appl. Pharmacol., 87:315–324.PubMedCrossRefGoogle Scholar
  35. Levesque, P. C., and Atchison, W. D., 1988, Effect of alteration of nerve terminal Ca2+ regulation on increased spontaneous quantal release of acetylcholine by methylmercury, Toxicol. Appl. Pharmacol., 94:55–65.PubMedCrossRefGoogle Scholar
  36. Macdonald, R. L., and Barker, J. L., 1979, Enhancement of GABA-mediated postsynaptic inhibition in cultured mammalian spinal cord neurons: A common mode of anticonvulsant action, Brain Res., 167:323–336.PubMedCrossRefGoogle Scholar
  37. Manalis, R. S., and Cooper, G. P., 1975, Evoked transmitter release increased by inorganic mercury at frog neuromuscular junction, Nature (London), 257:690–691.CrossRefGoogle Scholar
  38. Marco, L. A., Isaacson, L., and Torri, J. C., 1979, Effects of mercuric chloride on the resting membrane potentials of blue crab (Callinectes sapidus) muscle fibers, Toxicology, 12:41–46.PubMedCrossRefGoogle Scholar
  39. Misumi, J., 1979, Electrophysiological studies in vivo on peripheral nerve function and their application to peripheral neuropathy produced by organic mercury in rats. III. Effects of methylmercuric chloride on compound action potentials in the sciatic and tail nerve in rats, Kumamoto Med. J., 32:15–22.Google Scholar
  40. Miyakawa, T., Deshimaru, M., Sumiyoshi, S., Teraoka, A., Udo, N., Hattori, E., and Tatetsu, S., 1970, Experimental organic mercury poisoning—Pathological changes in peripheral nerves, Acta Neuropathol., 15:45–55.PubMedCrossRefGoogle Scholar
  41. Miyamoto, M. D., 1983, Hg2+ causes neurotoxicity at an intracellular site following entry through Na and Ca channels, Brain Res., 267:375–379.PubMedCrossRefGoogle Scholar
  42. Nakahiro, M., Yeh, J. Z., Brunner, E., and Narahashi, T., 1989, General anesthetics modulate GABA receptor channel complex in rat dorsal root ganglion neurons, Faseb J., 3:1850–1854.PubMedGoogle Scholar
  43. Nakahiro, M., Arakwara, O., and Narahashi, T., 1991. Modulation of GABA receptor-channel complex by alcohols. J. Pharmacol. Exp. Ther., in press.Google Scholar
  44. Neher, E., and Sakmann, B., 1976, Single-channel currents recorded from membrane of denervated frog muscle fibres, Nature (London), 260:779–802.CrossRefGoogle Scholar
  45. Nishio, M., and Narahashi, T. 1990, Ethanol enhancement of GABA-activated chloride current in rat dorsal root ganglion neurons, Brain Res., 518:283–286.PubMedCrossRefGoogle Scholar
  46. Norseth, T., and Clarkson, T., 1970, Studies on the biotransformation of 203Hg labeled methylmercury chloride in rats, Arch. Environ, Health, 21:717–727.CrossRefGoogle Scholar
  47. Ogata, N., Vogel, S. M., and Narahashi, T., 1988, Lindane but not deltamethrin blocks a component of GABA-activated chloride channels, Faseb J., 2:2895–2900.PubMedGoogle Scholar
  48. Omata, S., Sato, M., Sakimura, K., and Sugano, H., 1980, Time-dependent accumulation of inorganic mercury in subcellular fractions of kidney, liver, and brain of rats exposed to methylmercury, Arch. Toxicol., 44:231–241.PubMedCrossRefGoogle Scholar
  49. Oortgiesen, M., van Kleef, R. G. D. M., and Vijverberg, H. P. M., 1990a, Novel type of ion channel activated by Pb2+, Cd2+ and Al3+ in cultured mouse neuroblastoma cells, J. Membrane Biol., 113:261–268.CrossRefGoogle Scholar
  50. Oortgiesen, M., van Kleef, R. G. D. M., Bajnath, R. B., and Vijverberg, H. P. M., 1990b, Nanomolar concentrations of lead selectively block neuronal nicotinic acetylcholine responses in mouse neuroblastoma cells, Toxicol. Appl. Pharmacol. 103:165–174.PubMedCrossRefGoogle Scholar
  51. Paiement, J., and Joly, L. P., 1985, Effect of organic mercury on the electrical resistance of phosphatidylserine bilayers, Biochim. Biophys. Acta, 816:179–181.PubMedCrossRefGoogle Scholar
  52. Partridge, L. D., and Swandula, D., 1988, Calcium-activated non-specific cation channels, Trends in Neurosciences, 11:69–72.PubMedCrossRefGoogle Scholar
  53. Quandt, F. N., Kato, E., and Narahashi, T., 1982, Effects of methylmercury on electrical responses of neuroblastoma cells, NeuroToxicology, 3:205–220.PubMedGoogle Scholar
  54. Rustam, H., Von Burg, R., Amin-Zaki, L., and El Hassani, S., 1975, Evidence for a neuromuscular disorder in methylmercury poisoning, Arch. Environ. Health, 30:190–195.PubMedCrossRefGoogle Scholar
  55. Shrivastav, B. B., Brodwick, M. S., and Narahashi, T., 1976, Methylmercury: Effects on electrical properties of squid axon membranes, Life Sci., 18:1077–1082.PubMedCrossRefGoogle Scholar
  56. Skerfving, S., 1972, Organic mercury compounds. Relation between exposure and effects, in “Mercury in the Environment,” L. Friberg and J. Vostal, eds., 141–168, CRC Press, Cleveland.Google Scholar
  57. Skerritt, J. H., and Macdonald, R. L., 1984, Diazepam enhances the action but not the binding of the GABA analog THIP, Brain Res., 297:181–186.PubMedCrossRefGoogle Scholar
  58. Snyder, R. D., and Seelinge, D. F., 1976, Methylmercury poisoning clinical follow up and sensory nerve conduction studies, J. Neurol. Neurosurg. Psychol., 39:701–704.CrossRefGoogle Scholar
  59. Somjen, G. G., Herman, S. P., and Klein, R., 1973, Electrophysiology of methyl mercury poisoning, J. Pharmacol. Exp. Ther., 186:579–592.PubMedGoogle Scholar
  60. Swandulla, D., and Lux, H. D., 1985, Activation of a nonspecific cation conductance by intracellular Ca2+ elevation in bursting pacemaker neurons of Helix pomatia, J. Neurophysiol., 54:1430–1444.PubMedGoogle Scholar
  61. Takeuchi, T., Morikawa, N., Matsumoto, H., and Shiraishi, Y., 1962, A pathological study of Minamata disease in Japan, Acta Neuropathol., 2:40–57.CrossRefGoogle Scholar
  62. Takeuchi, T., Matsumoto, H., Sasaki, M., Kambara, T., Shiraishi, Y., Hirata, Y., Nobuhiro, M., and Ito, H., 1968, Pathology of Minamata disease, Kumamato Med. J., 34:521–524.Google Scholar
  63. Traxinger, D. L., and Atchison, W. D., 1987, Comparative effects of divalent cations on the methylmercury-induced alterations of acetycholine release, J. Pharmacol. Exp. Ther., 240:451–459.PubMedGoogle Scholar
  64. Von Burg, R., and Rustam, H., 1974, Conduction velocities in methylmercury poisoned patients, Bull. Environ. Contam. Toxicol., 12:81–85.CrossRefGoogle Scholar
  65. Von Burg, R., Northington, F. K., and Shamoo, A., 1980, Methylmercury inhibition of rat brain muscarinic receptors, Toxicol. Appl. Pharmacol., 53:285–292.CrossRefGoogle Scholar
  66. Weinreich, D., and Wonderlin, W. F., 1987, Copper activates a unique inward current in molluscan neurones, J. Physiol. (London), 394:429–443.Google Scholar
  67. Yellen, G., 1982, Single Ca2-activated nonselective cation channels in neuroblastoma, Nature (London) 296:357–359.CrossRefGoogle Scholar
  68. Yoshino, Y, Mozai, T., and Nakao, K., 1966, Distribution of mercury in the brain and its subcellular units in experimental organic mercury poisonings, J. Neurochem., 13:397–406.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1991

Authors and Affiliations

  • Toshio Narahashi
    • 1
  • Osamu Arakawa
    • 1
  • Masanobu Nakahiro
    • 1
  1. 1.Department of PharmacologyNorthwestern University Medical SchoolChicagoUSA

Personalised recommendations