Skip to main content
SpringerLink
Log in

GABA receptor-channel complex as a target site of Mercury, copper, zinc, and lanthanides

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

Summary

1. The GABAA receptor-chloride channel complex has been shown to be modulated by a variety of chemicals. Scores of chemicals with diverse and unrelated structures augment the GABA-induced chloride current, while some other chemicals suppress the current. Certain heavy metals and a variety of polyvalent cations increase or decrease the current in a potent and efficacious manner.

2. We have studied the mechanisms whereby mercury, copper, zinc, and lanthanides modulate the GABA system by whole-cell and single-channel patch clamp techniques as applied to the rat dorsal root ganglion neurons in primary culture.

3. Mercuric chloride augmented the GABA-induced current to 115% of control at 0.1 µM and to 270% of control at 100 µM. It also generated a slowly developing inward current carried by a variety of ions. In contrast, methylmercury suppressed the GABA-induced current. The potent stimulation of the GABA system by mercuric chloride is deemed important in mercury intoxication.

4. Copper and zinc suppressed the GABA-induced current with an EC50 of 16 and 19 µM, respectively. They bound to a common site on the external surface of the GABA receptor-channel complex.

5. Lanthanum augmented the GABA-induced current with an EC50 of 230 µM by increasing the affinity of the receptor for GABA. It bound to a site on or near the external surface of the GABA receptor-channel complex which is different from the sites for GABA, barbiturates, benzodiazepines, picrotoxin, and copper/zinc.

6. Six other lanthanides with larger atomic numbers also exerted the same stimulatory effect with their efficacies increasing with the atomic number.

7. Single-channel analyses have revealed that the augmentation of whole-cell current by terbium, a lanthanide, is due to three actions: an increase in the overall mean open time, a decrease in the overall mean closed time, and an increase in the overall mean burst time.

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

  • Abd-Elfattah, A.-S. A., and Shamoo, A. E. (1981). Regeneration of a functionally active rat brain muscarinic receptor byd-penicillamine after inhibition with methylmercury and mercuric chloride. Evidence for essential sulfhydryl groups in muscarinic receptor binding sites.Mol. Pharmacol. 20:492–497.

    Google Scholar 

  • Arakawa, O., Nakahiro, M., and Narahashi, T. (1991). Mercury modulation of GABA-activated chloride channels and non-specic cation channels in rat dorsal root ganglion neurons.Brain Res. 551:58–63.

    Google Scholar 

  • Assaf, S. Y., and Chung, S. H. (1984). Release of endogenous Zn2+ from brain tissue during activity.Nature 308:734–736.

    Google Scholar 

  • Atchison, W. D. (1986). Extracellular calcium-dependent and independent effects of methylmercury on spontaneous and potassium-evolked release of acetylcholine at the neuromuscular junction.J. Pharmacol. Exp. Ther. 237:672–680.

    Google Scholar 

  • Atchison, W. D. (1987). Effects of activation of sodium and calcium entry on spontaneous release of acetylcholine induced by methylmercuryJ. Pharmacol. Exp. Ther. 241:131–139.

    Google Scholar 

  • Atchison, W. D., and Narahashi, T. (1982). Methylmercury-induced depression of neuromuscular transmission in the rat.Neurotoxicology 3:37–50.

    Google Scholar 

  • Atchison, W. D., Joshi, U., and Thornburg, J. E. (1986). Irreversible suppression of calcium entry into nerve terminals by methylmercury.J. Pharmacol. Exp. Ther. 238:618–624.

    Google Scholar 

  • 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.

    Google Scholar 

  • Bormann, J., Hamill, O. P., and Sakmann, B. (1987). Mechanisms of anion permeation through channels gated by glycine andγ-aminobutyric acid in mouse cultured spinal neurones.J. Physiol. 385:243–286.

    Google Scholar 

  • Catterall, W. A. (1980). Neurotoxins that act on voltage-sensitive sodium channels in excitable membranes.Annu. Rev. Pharmacol. Toxicol. 20:15–43.

    Google Scholar 

  • Celentano, J. J., Gibbs, T. T., and Farb, D. H. (1988). Ethanol potentiates GABA- and glycine-induced chloride currents in chick spinal cord neurons.Brain Res. 455:377–380.

    Google Scholar 

  • Celentano, J. J., Gyenes, M., Gibbs, T. T., and Farb, D. H. (1991). Negative modulation of theγ-aminobutyric acid responses by extracellular zinc.Mol. Pharmacol. 40:766–773.

    Google Scholar 

  • Cole, K. S. (1949). Dynamic electrical characteristics of the squid axon membrane.Arch. Sci. Physiol. 3:253–258.

    Google Scholar 

  • Colquhoun, D., and Sigworth, F. J. (1983). Fitting and statistical analysis of single-channel records. In Sakmann, B., and Neher, E. (eds.),Single-Channel Recordings, Plenum Press, New York, pp. 191–263.

    Google Scholar 

  • Evans, C. H. (1983). Interesting and useful biochemical properties and lanthanides.Trends Biochem. Sci. 8:445–449.

    Google Scholar 

  • Fenwick, E. M., Marty, A., and Neher, E. (1982). A patch-clamp study of bovine chromaffin cells and of their sensitivity to acetylcholine.J. Physiol. 331:577–597.

    Google Scholar 

  • Hahne, H. C. H., and Kroontje, W. (1973). Significance of pH and chloride concentration on behavior of heavy metal pollutants: Mercury (II), cadmium (II), zinc (II), and lead (II).J. Environ. Qual. 2:444–450.

    Google Scholar 

  • 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.

    Google Scholar 

  • Hille, B. (1975). The receptor for tetrodotoxin and saxitoxin. A structural hypothesis.Biophys. J. 15:615–619.

    Google Scholar 

  • Hille, B. (1992).Ionic Channels of Excitable Membranes, Sinauer Associates, Sunderland, MA.

    Google Scholar 

  • Hodgkin, A. L., and Huxley, A. F. (1952a). Currents carried by sodium and potassium ions through the membrane of giant axon ofLoligo.J. Physiol. 116:449–472.

    Google Scholar 

  • Hodgkin, A. L., and Huxley, A. F. (1952b). The components of membrane conductance in the giant axon ofLoligo.J. Physiol. 116:473–496.

    Google Scholar 

  • Hodgkin, A. L., and Huxley, A. F. (1952c). The dual effect of membrane potential on sodium conductance in the giant axon ofLoligo.J. Physiol. 116:497–506.

    Google Scholar 

  • Hodgkin, A. L., and Huxley, A. F. (1952d). A quantitative description of membrane current and its application to conduction and excitation in nerve.J. Physiol. 117:500–544.

    Google Scholar 

  • Hodgkin, A. L., Huxley, A. F., and Katz, B. (1952). Measurement of current-voltage relations in the membrane of the giant axon ofLoligo.J. Physiol. 116:424–448.

    Google Scholar 

  • 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.

    Google Scholar 

  • Juang, M. S., and Yonemura, K. (1975). Increased spontaneous transmitter release from presynaptic nerve terminal by methylmercuric chloride.Nature 256:211–213.

    Google Scholar 

  • Kaneko, A., and Tachibana, M. (1986). Blocking effects of cobalt and related ions on theγ-aminobutyric acid-induced current in turtle retinal cones.J. Physiol. 373:463–479.

    Google Scholar 

  • Kardos, J., Kovács, I., Hajós, F., Kálmán, M., and Simonyi, M. (1989). Nerve endings from rat brain tissue release copper depolarization. A possible role in regulating neuronal excitability.Neurosci. Lett. 103:139–144.

    Google Scholar 

  • Kiskin, N. A., Krishtal, O. A., Tsyndrenko, A.-Y., and Akaike, N. (1986). Are sulphydryl groups essential for the function of the glutamate-operated receptor-ionophore complex?Neurosci. Lett. 66:305–310.

    Google Scholar 

  • Komulainen, H., and Tuomisto, J. (1981). Interference of methyl mercury with monoamine uptake and release in rat brain synaptosomes.Acta Pharmacol. Toxicol. 48:214–222.

    Google Scholar 

  • Kostial, K., and Landeka, M. (1975). The action of mercury ions on the release of acetylcholine from presynaptic nerve endings.Experientia 31:834–835.

    Google Scholar 

  • Krishtal, O. A., and Pidoplichko, V. I. (1980). A receptor for protons in the nerve cell membrane.Neuroscience 5:2325–2327.

    Google Scholar 

  • Legendre, P., and Westbrook, G. L. (1991). Noncompetitive inhibition ofγ-aminobutyric acidA channels by Zn.Mol. Pharmacol. 39:267–274.

    Google Scholar 

  • Levesque, P. C., and Atchison, W. D. (1987). Interactions of mitochondrial inhibitors with methylmercury on spontaneous quantal release of acetylcholine.Toxicol. Appl. Pharmacol. 87:315–324.

    Google Scholar 

  • Luckey, T. D., and Venugopal, B. (1977).Metal Toxicity in Mammals. 1, Plenum Press, New York.

    Google Scholar 

  • Ma, J. Y., and Narahashi, T. (1993a). Differential modulation of GABAA receptor-channel complex by polyvalent cations in rat dorsal root ganglion neurons.Brain Res. 607:222–232.

    Google Scholar 

  • Ma, J. Y., and Narahashi, T. (1993b). Enhancement ofγ-aminobutyric acid-activated chloride channel currents by lanthanides in rat dorsal root ganglion neurons.J. Neurosci. 13:4872–4879.

    Google Scholar 

  • Ma, J. Y., Reuveny, E., and Narahashi, T. (1994). Terbium modulation of singleγ-aminobutyric acid-activated chloride channels in rat dorsal root ganglion neurons.J. Neurosci. 14:3835–3841.

    Google Scholar 

  • Macdonald, R. L., Rogers, C. J., and Twyman, R. E. (1989). Barbiturate regulation of kinetic properties of the GABAA receptor channel of mouse spinal neurones in culture.J. Physiol. 417:483–500.

    Google Scholar 

  • Manalis, R. S., and Cooper, G. P. (1975). Evoked transmitter release increased by inorganic mercury at frog neuromuscular junction.Nature 257:690–691.

    Google Scholar 

  • McKay, S. J., Reynolds, J. N., and Racz, W. J. (1986a). Differential effects of methylmercuric chloride and mercuric chloride on thel-glutamate and potassium-evoked release of [3H]dopamine from mouse striatal slices.Can. J. Physiol. Pharmacol. 64:656–660.

    Google Scholar 

  • McKay, S. J., Reynolds, J. N., and Racz, W. J. (1986b). Effects of mercury compounds on the spontaneous and potassium-evoked release of [3H]dopamine from mouse striatal slices.Can. J. Physiol. Pharmacol. 64:1507–1514.

    Google Scholar 

  • McLaughlin, S., Szabo, G., and Eisenman, G. (1971). Divalent ions and the surface potential of charged phospholipid membranes.J. Physiol. 58:667–687.

    Google Scholar 

  • Miyamoto, M. D. (1983). Hg2+ causes neurotoxicity at an intracellular site following entry through Na and Ca channels.Brain Res. 267:375–379.

    Google Scholar 

  • Mozhayeva, G. N., and Naumov, A. P. (1972). Tetraethylammonium ion inhibition of potassium conductance of the nodal membrane.Biochim. Biophys. Acta 290:248–255.

    Google Scholar 

  • Nakazato, Y., Asano, T., and Ohga, A. (1979). Thein vitro effect of mercury compounds on noradrenaline output from guinea pig vas deferens.Toxicol. Appl. Pharmacol. 48:171–177.

    Google Scholar 

  • Narahashi, T. (1974). Chemicals as tools in the study of excitable membranes.Physiol. Rev. 54:813–889.

    Google Scholar 

  • Narahashi, T. (1988). Mechanism of tetrodotoxin and saxitoxin action. InHandbook of Natural Toxins, Vol. 3. Marine Toxins and Venoms (A. T. Tu, Ed.), Marcel Dekker, New York, pp. 185–210.

    Google Scholar 

  • Narahashi, T. (1992). Overview of toxins and drugs as tools to study excitable membrane ion channels. II. Transmitter-activated channels. InMethods in Enzymology, Vol. 207, Ion Channels (B. Rudy and L. E. Iverson, Eds.), Academic Press, San Diego, CA, pp. 643–658.

    Google Scholar 

  • Narahashi, T., and Herman, M. D. (1992). Overview of toxins and drugs as tools to study excitable membrane ion channels. I. Voltage-activated channels. InMethods in Enzymology, Vol. 207, Ion Channels (B. Rudy and L. E. Iverson Eds.), Academic Press, San Diego, CA, pp. 620–643.

    Google Scholar 

  • Narahashi, T., Deguchi, T., Urakawa, N., and Ohkubo, Y. (1960). Stabilization and rectification of muscle fiber membrane by tetrodotoxin.Am. J. Physiol. 198:934–938.

    Google Scholar 

  • Narashashi, T., Moore, J. W., and Scott, W. R. (1964). Tetrodotoxin blockage of sodium conductance increase in lobster giant axons.J. Gen. Physiol. 47:965–974.

    Google Scholar 

  • Narahashi, T., Anderson, N. C., and Moore, J. W. (1967). Comparison of tetrodotoxin and procaine in internally perfused squid giant axons.J. Gen. Physiol. 50:1413–1428.

    Google Scholar 

  • Nayeem, N., Green, T. P., Martin, I. L., and Barnard, E. A. (1994). Quaternary structure of the native GABAA receptor determined by electron microscopic image analysis.J. Neurochem. 62:815–818.

    Google Scholar 

  • Neher, E., and Sakmann, B. (1976). Single-channel currents recorded from membrane of denervated frog muscle fibres.Nature 260:779–802.

    Google Scholar 

  • Noda, M., Takahashi, H., Tanabe, T., Toyosata, M., Furutani, Y., Hirose, T., Asai, M., Inayama, S., Miyata, T., and Numa, S. (1982). Primary structure of theα-subunit precursor ofTorpedo californica acetylcholine deduced from cDNA sequence.Nature 299:793–797.

    Google Scholar 

  • Noda, M., Takahashi, H., Tanabe, T., Toyosata, M., Kikyotani, S., Hirose, T., Asai, M., Takashima, H., Inayama, S., Miyata, T., and Numa, S. (1983). Primary structures ofβ- andδ-subunit precursors ofTorpedo californica acetylcholine receptor deduced from cDNA sequences.Nature 301:251–255.

    Google Scholar 

  • 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.

    Google Scholar 

  • Ohmori, H., and Yoshii, M. (1977). Surface potential reflected in both gating and permeation mechanism of sodium and calcium channels of the tunicate egg cell membrane.J. Physiol. 267:429–463.

    Google Scholar 

  • Olsen, R. W., and Tobin, A. J. (1990). Molecular biology of GABAA receptors.FASEB J. 4:1469–1480.

    Google Scholar 

  • Quandt, F. N., Kato, E., and Narahashi, T. (1982). Effects of methylmercury on electrical responses of neuroblastoma cells.Neurotoxicology 3:205–220.

    Google Scholar 

  • Ritchie, J. M. (1979). A pharmacological approach to the structure of sodium channels in myelinated axons.Annu. Rev. Neurosci. 2:341–362.

    Google Scholar 

  • Schwartz, R. D. (1988). The GABAA receptor-gated ion channel: Biochemical and pharmacological studies of structure and function.Biochem. Pharmacol. 37:3369–3375.

    Google Scholar 

  • Shafer, T. J., and Atchison, W. D. (1990). Methylmercury blocks currents mediated by voltage-dependent Ca channels in nerve growth factor-differentiated pheochromocytoma cells.Soc. Neurosci. Abstr. 16:512.

    Google Scholar 

  • Shafer, T. J., and Atchison, W. D. (1991). Methylmercury blocks N-and L-type Ca++ channels in nerve growth factor-differentiated pheochromocytoma (PC12) cells.J. Pharmacol. Exp. Ther. 258:149–157.

    Google Scholar 

  • Shanes, A. M., Freygang, H., Grundfest, H., and Amatniek, E. (1959). Anesthetic and calcium action in the voltage clamped squid giant axon.J. Gen. Physiol. 42:793–802.

    Google Scholar 

  • Shrivastav, B. B., Brodowick, M. S., and Narahashi, T. (1976). Methylmercury: Effects on electrical properties of squid axon membranes.Life Sci. 18:1077–1082.

    Google Scholar 

  • Sieghart, W. (1992). GABAA receptors: Ligand-gated Cl− ion channels modulated by multiple drug-binding sites.Trends Pharmacol. Sci. 13:446–450.

    Google Scholar 

  • Smart, T. G. (1992). A novel modulatory binding site for zinc on the GABAA receptor complex in cultured rat neurones.J. Physiol. 447:587–625.

    Google Scholar 

  • Study, R. E., and Barker, J. L. (1981). Diazepam and (−)-pentobarbital: Fluctuation analysis reveals different mechanisms for potentiation ofγ-aminobutyric acid responses in cultured central neurons.Proc. Natl. Acad. Sci. USA 78:7180–7184.

    Google Scholar 

  • Sumikawa, K., Houghton, M., Emtage, J. S., Richards, B. M., and Barnard, E. A. (1981). Active multi-subunit ACh receptor assembled by translation of heterologous mRNA inXenopus oocytes.Nature 292:862–864.

    Google Scholar 

  • Takeuchi, T., Morikawa, N., Matsumoto, H., and Shiraishi, Y. (1962). A pathological study of Minamata disease in Japan.Acta Neuropathol. 2:40–57.

    Google Scholar 

  • Tasaki, I., and Hagiwara, S. (1957). Demonstration of two stable potential states in the squid giant axon under tetraethylammonium chloride.J. Gen. Physiol. 40:859–885.

    Google Scholar 

  • Taylor, R. E. (1959). Effect on procaine on electrical properties of squid axon membrane.Am. J. Physiol. 196:1071–1078.

    Google Scholar 

  • Traxinger, D. L., and Atchison, W. D. (1987). Comparative effects of divalent cations on the methylmercury-induced alterations of acetylcholine release.J. Pharmacol. Exp. Ther. 240:451–459.

    Google Scholar 

  • Twyman, R. E., and Macdonald, R. L. (1992). Neurosteroid regulation of GABAA receptor single channel kinetic properties.J. Physiol. 456:215–245.

    Google Scholar 

  • Twyman, R. E., Roger, C. J., and Macdonald, R. L. (1989). Differential regulation ofγ-aminobutyric acid receptor channels by diazepam and phenobarbital.Ann. Neurol. 25:213–220.

    Google Scholar 

  • Umbach, J. A., and Gundersen, C. B. (1989). Mercuric ions are potent noncompetitive antagonists of human brain kainate receptors expressed inXenopus oocytes.Mol. Pharmacol. 36:582–588.

    Google Scholar 

  • Vicini, S., Mienville, J., and Costa, E. (1987). Actions of benzodiazepine andβ-carboline derivatives onγ-aminobutyric acid-activated Cl− channels recorded from membrane patches of neonatal rat cortical neurons in culture.J. Pharmacol. Exp. Ther. 243:1195–1201.

    Google Scholar 

  • Vogel, W. (1974). Calcium and lanthanum effects at the nodal membrane.Pflügers Arch. 350:25–39.

    Google Scholar 

  • Von Burg, R., Northington, F. K., and Shamoo, A. (1980). Methylmercury inhibition of rat brain muscarinic receptors.Toxicol. Appl. Pharmacol. 53:285–292.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Northwestern University Medical School, 60611, Chicaco, Illinois

    Toshio Narahashi, Jenny Yan Ma, Osamu Arakawa, Eitan Reuveny & Masanobu Nakahiro

  2. Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, 303 East Chicago Avenue, 60611-3008, Chicago, Illinois

    Toshio Narahashi

  3. Department of Pharmacology, SJ-30, University of Washington, 98195, Seattle, Washington

    Jenny Yan Ma

  4. Faculty of Fishery, University of Kagoshima, Kagoshima, Japan

    Osamu Arakawa

  5. Howard Hughes Medical Institute, University of California at San Francisco, 94143, San Francisco, California

    Eitan Reuveny

  6. National Hospital Shou-raii-soh, 2815 Koizumi-cho, Yamato-Kooriyama, 639-11, Nara, Japan

    Masanobu Nakahiro

Authors
  1. Toshio Narahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jenny Yan Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Osamu Arakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eitan Reuveny
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Masanobu Nakahiro
    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

Narahashi, T., Ma, J.Y., Arakawa, O. et al. GABA receptor-channel complex as a target site of Mercury, copper, zinc, and lanthanides. Cell Mol Neurobiol 14, 599–621 (1994). https://doi.org/10.1007/BF02088671

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02088671

Key words

Search

Navigation