Rotenone reduces Mg2+-dependent block of NMDA currents in substantia nigra dopamine neurons

Yan Na Wu, Steven Johnson

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Rotenone is a pesticide that has been successfully used to produce a rodent model of Parkinson's disease. We reported previously that rotenone potently augmented N-methyl-d-aspartate (NMDA)-evoked currents in rat dopamine neurons via a tyrosine kinase-dependent mechanism. In this study, we investigated the effect of rotenone on the current-voltage relationship of NMDA-induced currents in substantia nigra zona compacta neurons recorded with whole-cell patch pipettes in slices of rat brain. In a physiologic concentration of extracellular Mg2+ (1.2 mM), a 30 min perfusion with rotenone (100 nM) produced a marked increase in current evoked by bath application of NMDA (30 μM), especially when measured at relatively hyperpolarized currents. In the presence of rotenone, NMDA currents lost the characteristic region of negative-slope conductance that is normally produced by voltage-dependent block by Mg2+. The voltage-dependent effect of rotenone on NMDA currents was mimicked by a low extracellular concentration of Mg2+ (0.2 mM) and was antagonized by a high level of Mg2+ (6.0 mM). Moreover, we report that the tyrosine kinase inhibitor genistein blocked the ability of rotenone to augment NMDA receptor currents. These results suggest that rotenone potentiates NMDA currents by a tyrosine kinase-dependent process that attenuates voltage-dependent Mg2+ block of NMDA-gated channels. These results support the hypothesis that an excitotoxic mechanism might participate in rotenone-induced toxicity of midbrain dopamine neurons.

Original languageEnglish (US)
Pages (from-to)320-325
Number of pages6
JournalNeuroToxicology
Volume30
Issue number2
DOIs
StatePublished - Mar 2009

Fingerprint

Rotenone
Dopaminergic Neurons
Substantia Nigra
Aspartic Acid
Neurons
Dopamine
Protein-Tyrosine Kinases
Electric potential
Rats
Genistein
Induced currents
Herpes Zoster
Mesencephalon
Baths
Pesticides
Parkinson Disease
Toxicity
Rodentia
Brain
Perfusion

Keywords

  • Brain slice
  • Dopamine
  • Magnesium
  • N-methyl-d-aspartate
  • Tyrosine kinase
  • Voltage-dependent

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

Cite this

Rotenone reduces Mg2+-dependent block of NMDA currents in substantia nigra dopamine neurons. / Wu, Yan Na; Johnson, Steven.

In: NeuroToxicology, Vol. 30, No. 2, 03.2009, p. 320-325.

Research output: Contribution to journalArticle

@article{ce3e0a93175344f0a01a82a201ee8150,
title = "Rotenone reduces Mg2+-dependent block of NMDA currents in substantia nigra dopamine neurons",
abstract = "Rotenone is a pesticide that has been successfully used to produce a rodent model of Parkinson's disease. We reported previously that rotenone potently augmented N-methyl-d-aspartate (NMDA)-evoked currents in rat dopamine neurons via a tyrosine kinase-dependent mechanism. In this study, we investigated the effect of rotenone on the current-voltage relationship of NMDA-induced currents in substantia nigra zona compacta neurons recorded with whole-cell patch pipettes in slices of rat brain. In a physiologic concentration of extracellular Mg2+ (1.2 mM), a 30 min perfusion with rotenone (100 nM) produced a marked increase in current evoked by bath application of NMDA (30 μM), especially when measured at relatively hyperpolarized currents. In the presence of rotenone, NMDA currents lost the characteristic region of negative-slope conductance that is normally produced by voltage-dependent block by Mg2+. The voltage-dependent effect of rotenone on NMDA currents was mimicked by a low extracellular concentration of Mg2+ (0.2 mM) and was antagonized by a high level of Mg2+ (6.0 mM). Moreover, we report that the tyrosine kinase inhibitor genistein blocked the ability of rotenone to augment NMDA receptor currents. These results suggest that rotenone potentiates NMDA currents by a tyrosine kinase-dependent process that attenuates voltage-dependent Mg2+ block of NMDA-gated channels. These results support the hypothesis that an excitotoxic mechanism might participate in rotenone-induced toxicity of midbrain dopamine neurons.",
keywords = "Brain slice, Dopamine, Magnesium, N-methyl-d-aspartate, Tyrosine kinase, Voltage-dependent",
author = "Wu, {Yan Na} and Steven Johnson",
year = "2009",
month = "3",
doi = "10.1016/j.neuro.2009.01.002",
language = "English (US)",
volume = "30",
pages = "320--325",
journal = "NeuroToxicology",
issn = "0161-813X",
publisher = "Elsevier",
number = "2",

}

TY - JOUR

T1 - Rotenone reduces Mg2+-dependent block of NMDA currents in substantia nigra dopamine neurons

AU - Wu, Yan Na

AU - Johnson, Steven

PY - 2009/3

Y1 - 2009/3

N2 - Rotenone is a pesticide that has been successfully used to produce a rodent model of Parkinson's disease. We reported previously that rotenone potently augmented N-methyl-d-aspartate (NMDA)-evoked currents in rat dopamine neurons via a tyrosine kinase-dependent mechanism. In this study, we investigated the effect of rotenone on the current-voltage relationship of NMDA-induced currents in substantia nigra zona compacta neurons recorded with whole-cell patch pipettes in slices of rat brain. In a physiologic concentration of extracellular Mg2+ (1.2 mM), a 30 min perfusion with rotenone (100 nM) produced a marked increase in current evoked by bath application of NMDA (30 μM), especially when measured at relatively hyperpolarized currents. In the presence of rotenone, NMDA currents lost the characteristic region of negative-slope conductance that is normally produced by voltage-dependent block by Mg2+. The voltage-dependent effect of rotenone on NMDA currents was mimicked by a low extracellular concentration of Mg2+ (0.2 mM) and was antagonized by a high level of Mg2+ (6.0 mM). Moreover, we report that the tyrosine kinase inhibitor genistein blocked the ability of rotenone to augment NMDA receptor currents. These results suggest that rotenone potentiates NMDA currents by a tyrosine kinase-dependent process that attenuates voltage-dependent Mg2+ block of NMDA-gated channels. These results support the hypothesis that an excitotoxic mechanism might participate in rotenone-induced toxicity of midbrain dopamine neurons.

AB - Rotenone is a pesticide that has been successfully used to produce a rodent model of Parkinson's disease. We reported previously that rotenone potently augmented N-methyl-d-aspartate (NMDA)-evoked currents in rat dopamine neurons via a tyrosine kinase-dependent mechanism. In this study, we investigated the effect of rotenone on the current-voltage relationship of NMDA-induced currents in substantia nigra zona compacta neurons recorded with whole-cell patch pipettes in slices of rat brain. In a physiologic concentration of extracellular Mg2+ (1.2 mM), a 30 min perfusion with rotenone (100 nM) produced a marked increase in current evoked by bath application of NMDA (30 μM), especially when measured at relatively hyperpolarized currents. In the presence of rotenone, NMDA currents lost the characteristic region of negative-slope conductance that is normally produced by voltage-dependent block by Mg2+. The voltage-dependent effect of rotenone on NMDA currents was mimicked by a low extracellular concentration of Mg2+ (0.2 mM) and was antagonized by a high level of Mg2+ (6.0 mM). Moreover, we report that the tyrosine kinase inhibitor genistein blocked the ability of rotenone to augment NMDA receptor currents. These results suggest that rotenone potentiates NMDA currents by a tyrosine kinase-dependent process that attenuates voltage-dependent Mg2+ block of NMDA-gated channels. These results support the hypothesis that an excitotoxic mechanism might participate in rotenone-induced toxicity of midbrain dopamine neurons.

KW - Brain slice

KW - Dopamine

KW - Magnesium

KW - N-methyl-d-aspartate

KW - Tyrosine kinase

KW - Voltage-dependent

UR - http://www.scopus.com/inward/record.url?scp=61849083067&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=61849083067&partnerID=8YFLogxK

U2 - 10.1016/j.neuro.2009.01.002

DO - 10.1016/j.neuro.2009.01.002

M3 - Article

VL - 30

SP - 320

EP - 325

JO - NeuroToxicology

JF - NeuroToxicology

SN - 0161-813X

IS - 2

ER -