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

Dietrich Busselberg, D. Michael, B. Platt

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

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+.

Original languageEnglish
Pages (from-to)711-722
Number of pages12
JournalCellular and Molecular Neurobiology
Volume14
Issue number6
DOIs
Publication statusPublished - Dec 1994
Externally publishedYes

Fingerprint

Calcium Channels
Aspartic Acid
Electric potential
Glycine
Calcium
Inhibitory Concentration 50
Ion Channels
Neurons
Potassium
Sodium

Keywords

  • channel blockade
  • lead (Pb)
  • metal neurotoxicity
  • NMDA receptor
  • voltage-activated calcium channel currents

ASJC Scopus subject areas

  • Neuroscience(all)
  • Genetics
  • Clinical Biochemistry
  • Cell Biology

Cite this

Pb2+ reduces voltage- and N-methyl-d-aspartate (NMDA)-activated calcium channel currents. / Busselberg, Dietrich; Michael, D.; Platt, B.

In: Cellular and Molecular Neurobiology, Vol. 14, No. 6, 12.1994, p. 711-722.

Research output: Contribution to journalArticle

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abstract = "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+.",
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N2 - 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+.

AB - 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+.

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