Skip to main content
SpringerLink
Log in

Pb2+ reduces voltage- andN-methyl-d-aspartate (NMDA)-activated calcium channel currents

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

Summary

1. While intracellular calcium concentrations are closely regulated, two types of ion channels in neurons allow calcium influx: both voltage-activated and NMDA-activated channels are significantly permeable to calcium. In this study we compare the effects of lead (Pb2+) on currents carried through voltage-activated calcium channels and NMDA-activated channels.

2. Pb2+ reduces voltage-activated calcium channel currents elicited by a voltage jump from −80 to 0 mV at 0.1 to 1 µM, with an IC50 of 0.64 µM and a Hill slope of 1.22. This effect was partially reversible and not voltage dependent. Sodium and potassium currents were relatively unaffected at Pb2+ concentrations sufficient to block calcium channel currents by more than 80%. Pb2+ is, thus, a potent, reversible and selective blocker of voltage-dependent calcium channel currents.

3. A fast reversible and slow irreversible blocking action of Pb2+ was found on NMDA-activated currents. When Pb2+ was applied simultaneously with aspartate and glycine (Asp/Gly), the inward currents were rapidly and reversibly reduced in a dose-dependent manner with a minimum effective concentration below 2 µM and a total blockade (>80%) with 100 µM Pb2+. The IC50 was ∼45 µM and the Hill coefficient 1.1. Preincubation with 50 µM Pb2+ resulted in a greater reduction in the response to Asp/Gly/Pb2+. This effect was reversed within 2 to 5 sec of wash. The lack of voltage dependence suggests that Pb2+ does not block the channel but rather alters the binding of agonists. Prolonged superfusion of a cell with the Asp/Gly/Pb2+-containing external solution resulted in a slow and irreversible decrease in the Asp/Gly activated current. No clear threshold concentration is found for this slow and irreversible effect of Pb2+. This slow action might be more important for neurotoxic effects of Pb2+.

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

  • Alkondon, M., Costa, A. C., Radhakrishnan, V., Aronstam, R. S., and Albuquerque, E. X. (1990). Selective blockade of NMDA-activated channel currents may be implicated in learning deficits caused by lead.FEBS Lett. 261:124–130.

    Google Scholar 

  • Altmann, L., Sveinsson, K., and Wiegand, H. (1991). Long-term potentiation in rat hippocampal slices is impaired following acute lead perfusion.Neurosci. Lett. 128:109–112.

    Google Scholar 

  • Altmann, L., Weinsberg, F., Sveinsson, K., Lilienthal, H., Wiegand, H., and Winneke, G. (1993). Impairment of long-term potentiation and learning following chronic lead exposure.Toxicol. Lett. 66:105–112.

    Google Scholar 

  • Audesirk, G., and Audesirk, T. (1991). Effects of inorganic lead on voltage sensitive calcium channels in NIE-115 neuroblastoma cells.Neurotoxicology 12:519–528.

    Google Scholar 

  • Benetou Marantidou, A., Nakou, S., and Micheloyannis, J. (1988). Neurobehavioral estimation of children with life-long increased lead exposure.Arch. Environ. Health 43:392–395.

    Google Scholar 

  • Boland, L. M., and Dingledine, R. (1990). Multiple components of both transient and sustained barium currents in a rat dorsal root ganglion cell line.J. Physiol. Lond. 420:223–245.

    Google Scholar 

  • Brennan, R. J. W., and Cantrill, R. C. (1979). d-Aminolevulinic acid is a potent agonist for GABA receptors.Nature 280:514–515.

    Google Scholar 

  • Büsselberg, D., Evans, M. L., Rahmann, H., and Carpenter, D. O. (1991a). Effects of inorganic and triethyl lead and inorganic mercury on the voltage-activated calcium channel of Aplysia neurons.Neurotoxicology 12:733–744.

    Google Scholar 

  • Büsselberg, D., Evans, M. L., Rahmann, H., and Carpenter, D. O. (1991b). Lead and zinc block a voltage-activated calcium channel of Aplysia neurons.J. Neurophysiol. 65:786–795.

    Google Scholar 

  • Büsselberg, D., Evans, M. L., Haas, H. L., and Carpenter, D. O. (1993). Blockade of mammalian and invertebrate calcium channels by lead.Neurotoxicology 14:249–258.

    Google Scholar 

  • Büsselberg, D., Platt, B., Michael, D., Carpenter, D. O., and Haas, H. L. (1994a). Mammalian voltage-activated calcium channel currents are blocked by Pb2+, Zn2+, and Al3+.J. Neurophys. 71:1491–1497.

    Google Scholar 

  • Büsselberg, D., Domann, R., Wunder, L., and Haas, H. L. (1994b). Lead reduces calcium entry without passing the cell membrane of mammalian neurons: Fura 2 measurementsNeurosci. Abstr. 673:21.

    Google Scholar 

  • Carroll, P. T., Silbergeld, E. K., and Goldberg, A. M. (1977). Alteration of central cholinergic function by chronic lead acetate exposure.Biochem. Pharmacol. 26:397–402.

    Google Scholar 

  • Chad, J. E., and Eckert, R. (1986). An enzymatic mechanism for calcium current inactivation in dialysed Helix neurones.J. Physiol. Lond. 378:31–51.

    Google Scholar 

  • Chizhmakov, I. V., Kiskin, N. I., Krishal, O. A., and Tsyndrenko, A. Y. (1989). Glycine action on NMDA receptors in rat hippocampal neurons.Neurosci. Lett. 99:131–136.

    Google Scholar 

  • Christine, C. W., and Choi, D. W. (1990). Effects of zinc on NMDA-receptor mediated channel currents in cortical neurons.J. Neurosci. 10:108–116.

    Google Scholar 

  • Davis, S., Butcher, S. P., and Morris, R. G. (1992). The NMDA receptor antagonist D-2-amino-5-phosphonopentanoate (D-AP5) impairs spatial learning and LTP in vivo at intracerebral concentrations comparable to those that block LTP in vitro.J. Neurosci. 12:21–34.

    Google Scholar 

  • Evans, M. L., Büsselberg, D., and Carpenter, D. O. (1991). Pb2− blocks calcium currents of cultured dorsal root ganglion cells.Neurosci. Lett. 129:103–106.

    Google Scholar 

  • Fox, A. P., Nowycky, M. C., and Tsien, R. W. (1987a). Single-channel recordings of three types of calcium channels in chick sensory neurones.J. Physiol. Lond. 394:173–200.

    Google Scholar 

  • Fox, A. P., Nowycky, M. C., and Tsien, R. W. (1987b). Kinetic and pharmacological properties distinguishing three types of calcium currents in chick sensory neurones.J. Physiol. Lond. 394:149–172.

    Google Scholar 

  • Harris, E. W., Ganong, A. H., and Cotman, C. W. (1984). Longterm potentiation in the hippocampus involves activation of N-methyl-D-aspartate receptors.Brain Res. 323:132–137.

    Google Scholar 

  • Hernberg, S., and Nikkanen, J. (1970). Enzyme inhibition by lead under normal urban conditions.Lancet 1:63–64.

    Google Scholar 

  • Hernberg, S., Viekko, E., and Hasan, L. (1967). Red cell membrane ATPase in workers exposed to inorganic lead.Arch. Environ. Health 14:319–324.

    Google Scholar 

  • Holtzman, D., and Hsu, J. S. (1976). Early effects of inorganic lead on immature rat brain mitochondrial respiration.Pediatr. Res. 10:70–75.

    Google Scholar 

  • Hori, N., Büsselberg, D., Matthews, M. R., Parsons, P. J., and Carpenter, D. O. (1993). Lead blocks LTP by an action not at NMDA receptors.Exp. Neurol. 119:192–197.

    Google Scholar 

  • Lansman, J. B., Hess, P., and Tsien, R. W. (1986). Blockade of current through single calcium channels by Cd2+, Mg2+, and Ca2+. Voltage and concentration dependence of calcium entry into the pore.J. Gen. Physiol. 88:321–347.

    Google Scholar 

  • Legendre, P., and Westbrook, G. L. (1990). The inhibition of single N-methyl-D-aspartate-activated channels by zinc ions on cultured rat neurones.J. Physiol. Lond. 429:429–449.

    Google Scholar 

  • Leviton, A., Bellinger, D., Allred, E. N., Rabinowitz, M., Needleman, H., and Schoenbaum, S. (1993). Pre- and postnatal low-level lead exposure and children's dysfunction in school.Environ. Res. 60:30–43.

    Google Scholar 

  • Linás, R., Sugimori, M., Hillman, D. E., and Cherksey, B. (1992). Distribution and functional significance of the P-type, voltage-dependent Ca2+ channels in the mammalian central nervous system.Trends Neurosci. 15:351–355.

    Google Scholar 

  • Markovac, J., and Goldstein, G. W. (1988). Lead activates protein kinase C in immature rat brain microvessels.Toxicol. Appl. Pharmacol. 96:14–23.

    Google Scholar 

  • Mayer, M. L., and Westbrook, G. L. (1987). Permeation and block of N-methyl-aspartic acid receptor channels by divalent cations in mouse cultured central neurons.J. Physiol. Lond. 394:501–527.

    Google Scholar 

  • McMichael, A. J., Baghurst, P. A., Wigg, N. R., Vimpani, G. V., Robertson, E. F., and Roberts, R. J. (1988). Port Pirie Cohort Study: Environmental exposure to lead and children's abilities at the age of four years.N. Engl. J. Med. 319:468–475.

    Google Scholar 

  • Mintz, I. M., Adams, M. E., and Bean, B. P. (1992). P-type calcium channels in rat central and peripheral neurons.Neuron 9:85–95.

    Google Scholar 

  • Mintz, I. M., Venema, V. J., Swiderek, K. M., Lee, T. D., Bean, B. P., and Adams, M. E. (1992). P-type calcium channels blocked by the spider toxin omega-Aga-IVA.Nature 355:827–829.

    Google Scholar 

  • Murakami, K., Feng, G., and Chen, S. G. (1993). Inhibition of brain protein kinase C subtypes by lead.J. Pharmacol. Exp. Ther. 264:757–761.

    Google Scholar 

  • Nathan, R. D., Kanai, K., Clark, R. B., and Giles, W. (1988). Selective block of calcium current by lanthanum in single bullfrog atrial cells.J. Gen. Physiol. 91:549–572.

    Google Scholar 

  • Needleman, H. L., and Bellinger, D. (1991). The health effects of low level exposure to lead.Annu. Rev. Public Health 12:111–140.

    Google Scholar 

  • Needleman, H. L., Gunnoe, C., Leviton, A., Reed, R., Peresie, H., Maher, C., and Barrett, P. (1979). Deficits in psychologic and classroom performance of children with elevated dentine lead levels.N. Engl. J. Med. 300:689–695.

    Google Scholar 

  • Oyama, Y., Nishi, K., Yatani, A., and Akaike, N. (1982). Zinc current in Helix soma membrane.Comp. Biochem. Physiol. C 72:403–410.

    Google Scholar 

  • Padich, R. A., Dietrich, K. N., and Pearson, D. T. (1985). Attention, activity level, and lead exposure at 18 months.Environ. Res. 38:137–143.

    Google Scholar 

  • Pekel, M., Platt, B., and Büsselberg, D. (1993). Mercury (Hg2−) decreases voltage-gated calcium channel currents in rat DRG and Aplysia neurons.Brain Res. 632:121–126.

    Google Scholar 

  • Peters, S., Koh, J., and Choi, D. W. (1987). Zinc selectively blocks the action of N-methyl-D-aspartate on cortical neurons.Science 236:589–593.

    Google Scholar 

  • Piomelli, S., Seaman, C., and Zullow, D. (1982). Threshold for lead damage to heme synthesis in urban children.Proc. Natl. Acad. Sci. USA 79:3335–3339.

    Google Scholar 

  • Platt, B., Haas, H. L., and Büsselberg, D. (1993). Extracellular pH modulates aluminum-blockade of mammalian voltage-activated calcium channel currents.NeuroReport 4:1251–1254.

    Google Scholar 

  • Sather, W., Dieudonne, S., Macdonald, J., and Ascher, P. (1992). Activation and desensitization of N-methyl-D-aspartate receptors in nucleated outside-out patches from mouse neurons.J. Physiol. Lond. 450:643–672.

    Google Scholar 

  • Scroggs, R. S., and Fox, A. P. (1992). Calcium current variation between acutely isolated adult rat dorsal root ganglion neurons of different size.J. Physiol. Lond. 445:639–658.

    Google Scholar 

  • Simons, T. J. (1988). Calcium and neuronal function.Neurosurg. Rev. 11:119–129.

    Google Scholar 

  • Simons, T. J., and Pocock, G. (1987). Lead enters bovine adrenal medullary cells through calcium channels.J. Neurochem. 48:383–389.

    Google Scholar 

  • Swandulla, D., and Armstrong, C. M. (1989). Calcium channel block by cadmium in chicken sensory neurons.Proc. Natl. Acad. Sci. USA 86:1736–1740.

    Google Scholar 

  • Tomsig, J. L., and Suszkiw, J. B. (1990). Pb2+-induced secretion from bovine chromaffin cells: fura-2 as a probe for Pb2+.Am. J. Physiol. 259:762–768.

    Google Scholar 

  • Tsien, R. W., Hess, P., McCleskey, E. W., and Rosenberg, R. L. (1987). Calcium channel mechanisms of selectivity, permeation, and block.Annu. Rev. Biophys. Biophys. Chem. 16:265–290.

    Google Scholar 

  • Ujihara, H., and Albuquerque, E. X. (1992). Developmental change of the inhibition by lead of NMDA-activated currents in cultured hippocampal neurons.J. Pharmacol. Exp. Ther. 263:868–875.

    Google Scholar 

  • Uteshev, V., Büsselberg, D., and Haas, H. L. (1993). Pb2+ modulates the NMDA-receptor-channel complex.Naunyn Schmiedebergs Arch. Pharmacol. 347:209–213.

    Google Scholar 

  • Westbrook, G. L., and Mayer, M. L. (1987). Micromolar concentrations of Zn2+ antagonize NMDA and GABA responses of hippocampal neurons.Nature 328:640–643.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Heinrich-Heine Universität Düsseldorf, Physiologie II, Moorenstraße 5, D-40225, Düsseldorf, Germany

    D. Büsselberg, D. Michael & B. Platt

Authors
  1. D. Büsselberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Michael
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B. Platt
    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

Büsselberg, D., Michael, D. & Platt, B. Pb2+ reduces voltage- andN-methyl-d-aspartate (NMDA)-activated calcium channel currents. Cell Mol Neurobiol 14, 711–722 (1994). https://doi.org/10.1007/BF02088679

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02088679

Key words

Search

Navigation