TY - JOUR
T1 - Effects of the neuroprotective agent riluzole on the high voltage- activated calcium channels of rat dorsal root ganglion neurons
AU - Huang, Chao Sheng
AU - Song, Jin Ho
AU - Nagata, Keiichi
AU - Yeh, Jay Z.
AU - Narahashi, Toshio
N1 - Copyright:
Copyright 2007 Elsevier B.V., All rights reserved.
PY - 1997/9
Y1 - 1997/9
N2 - 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.
AB - 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.
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M3 - Article
C2 - 9316836
AN - SCOPUS:0030886021
SN - 0022-3565
VL - 282
SP - 1280
EP - 1290
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 3
ER -