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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

Effects of the Neuroprotective Agent Riluzole on the High Voltage-Activated Calcium Channels of Rat Dorsal Root Ganglion Neurons

Chao-Sheng Huang, Jin-Ho Song, Keiichi Nagata, Jay Z Yeh and Toshio Narahashi
Journal of Pharmacology and Experimental Therapeutics September 1997, 282 (3) 1280-1290;
Chao-Sheng Huang
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Jin-Ho Song
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Keiichi Nagata
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Jay Z Yeh
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Toshio Narahashi
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Abstract

The effects of riluzole, a neuroprotective drug, on high voltage-activated (HVA) calcium channels of rat dorsal root ganglion neurons were studied using the whole-cell patch-clamp technique. Riluzole inhibited HVA calcium channel currents in a dose-dependent, time-dependent and reversible manner. The apparent dissociation constants for riluzole inhibition of the transient and sustained components of the current were 42.6 and 39.5 μM, respectively. Riluzole accelerated the activation kinetics of calcium channels without affecting the voltage dependence of activation. It accelerated the fast component of deactivation kinetics without affecting the slow component. It also accelerated fast and slow inactivation kinetics of the HVA channels. However, only one of the two components in the steady-state inactivation curve for the HVA channels was shifted in the hyperpolarizing direction by riluzole, which indicates differential block of the multiple-type HVA channels. By use of the specific blockers nimodipine, ω-conotoxin GVIA and ω-agatoxin IVA, the HVA calcium channels were found to comprise L-type (10%), N-type (63%), P/Q-type (23%) and R-type (9%). Riluzole blocked N- and P/Q-type channels, but not L-type channel, with the order of efficacy of P/Q- > N- ≫ L-type channels. Riluzole inhibition of N- and P/Q-type calcium channels may result in reduced calcium influx at presynaptic terminals, which thereby decreases excessive excitatory neurotransmitter release, especially glutamate, a mechanism known to cause neuronal death in ischemic conditions.

Footnotes

  • Send reprint requests to: Dr. Toshio Narahashi, Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, 303 E. Chicago Avenue, Chicago, IL 60611-3008.

  • ↵1 This work was supported by National Institutes of Health Grant NS14144.

  • Abbreviations:
    HVA
    high voltage-activated
    DRG
    dorsal root ganglion
    DMEM
    Delbecco’s Modified Eagle Medium
    HEPES
    4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
    DMSO
    dimethylsulfoxide
    ω-CTx
    ω-conotoxin GVIA
    ω-Aga
    ω-agatoxin IVA
    I-V
    current-voltage
    NMDA
    N-methyl-d-aspartate, EGTA, [ethylenebis(oxyethylenenitrilo)]tetraacetic acid,
    • Received November 14, 1996.
    • Accepted May 9, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 282, Issue 3
1 Sep 1997
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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

Effects of the Neuroprotective Agent Riluzole on the High Voltage-Activated Calcium Channels of Rat Dorsal Root Ganglion Neurons

Chao-Sheng Huang, Jin-Ho Song, Keiichi Nagata, Jay Z Yeh and Toshio Narahashi
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1280-1290;

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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

Effects of the Neuroprotective Agent Riluzole on the High Voltage-Activated Calcium Channels of Rat Dorsal Root Ganglion Neurons

Chao-Sheng Huang, Jin-Ho Song, Keiichi Nagata, Jay Z Yeh and Toshio Narahashi
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1280-1290;
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