Riluzole-induced block of voltage-gated Na+ current and activation of BKCa channels in cultured differentiated human skeletal muscle cells

Wang, Ya-Jean; Lin, Ming‐Wei; Lin, Anan; Wu, Sheng‐Nan

doi:10.1016/j.lfs.2007.10.015

Cited by 52 publications

(41 citation statements)

References 39 publications

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“…3B) was not statistically different from the control current ( p Ͼ 0.05). Although riluzole activates calcium-dependent BK (Wang et al, 2008) and SK (Grunnet et al, 2001) potassium channels, the current recorded at Ϫ30 mV was not affected by the coapplication of apamin (200 nM) and paxilline (1 M), and the riluzole-activated current in the presence of these toxins was not significantly different from control (106.5 Ϯ 15.7 pA; n ϭ 6; p Ͼ 0.05) (Fig. 3C).…”

Section: Ionic Nature Of the Riluzole-activated Outward Currentmentioning

confidence: 89%

“…Riluzole inhibits voltage-activated sodium channels (Hebert et al, 1994;Reboreda et al, 2003;Wang et al, 2008), as reflected by the inhibition of transient and persistent sodium currents in cultured mSCG neurons (Lamas et al, 2009). As inhibition of a persistent sodium current would induce an apparent outward current, negative 15 mV voltage steps of 50 ms were applied at 0.4 Hz to track the variations in conductance induced by riluzole.…”

Section: Ionic Nature Of the Riluzole-activated Outward Currentmentioning

confidence: 99%

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Activation of TREK Currents by the Neuroprotective Agent Riluzole in Mouse Sympathetic Neurons

Cadaveira-Mosquera¹,

Ribeiro²,

Reboreda³

et al. 2011

J. Neurosci.

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ϩ channel) mRNA, and the expression of these three proteins was confirmed by immunocytochemistry in mSCG neurons. I RIL was enhanced by zinc, inhibited by barium and fluoxetine, but unaffected by quinine and ruthenium red, strongly suggesting that it was carried through TREK-1/2 channels. Consistently, a channel with properties identical with the heterologously expressed TREK-2 was recorded in most (75%) cell-attached patches. These results provide the first evidence for the expression of K2P channels in the mammalian autonomic nervous system, and they extend the impact of these channels to the entire nervous system.

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Section: Ionic Nature Of the Riluzole-activated Outward Currentmentioning

confidence: 89%

Section: Ionic Nature Of the Riluzole-activated Outward Currentmentioning

confidence: 99%

Activation of TREK Currents by the Neuroprotective Agent Riluzole in Mouse Sympathetic Neurons

Cadaveira-Mosquera¹,

Ribeiro²,

Reboreda³

et al. 2011

J. Neurosci.

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“…-activated K + current (I K(Ca) ) (8,9). However, little information is available regarding the underlying mechanism of actions of ranolazine on ion currents or membrane potential in neurons and endocrine or neuroendocrine cells.…”

Section: +mentioning

confidence: 99%

“…Some of agents known to block I Na (e.g., riluzole and vinpocetine) were noted to activate I K(Ca) (8,9). It was thus investigated whether ranolazine has any effect on I K(Ca) in these cells.…”

Section: Effects Of Ranolazine On I K(ca) In Gh 3 Cellsmentioning

confidence: 99%

Effects of Ranolazine, a Novel Anti-anginal Drug, on Ion Currents and Membrane Potential in Pituitary Tumor GH3 Cells and NG108-15 Neuronal Cells

Chen

Peng

et al. 2009

J Pharmacol Sci

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Abstract. Ranolazine, a piperazine derivative, is currently approved for the treatment of chronic angina. However, its ionic mechanisms in other types of cells remain unclear, although it is thought to be a selective blocker of late Na + current. This study was conducted to evaluate the possible effects of ranolazine on Na, and Ca 2+-activated K + current (I K(Ca) ) in pituitary tumor (GH 3 ) cells. Ranolazine depressed the transient and late components of I Na with different potencies. This drug exerted an inhibitory effect on I K(IR) with an IC 50 value of 0.92 μM, while it slightly inhibited I K(DR) and I K(Ca) . It shifted the steady-state activation curve of I K(IR) to more positive potentials with no change in the gating charge of the channel. Ranolazine (30 μM) also reduced the activity of large-conductance Ca 2+-activated K + channels in HEK293T cells expressing α-hSlo. Under current-clamp conditions, low concentrations (e.g., 1 μM) of ranolazine increased the firing of action potentials, while at high concentrations (≥10 μM), it diminished the firing discharge. The exposure to ranolazine also suppressed I Na and I K(IR) effectively in NG108-15 neuronal cells. Our study provides evidence that ranolazine could block multiple ion currents such as I Na and I K(IR) and suggests that these actions may contribute to some of the functional activities of neurons and endocrine or neuroendocrine cells in vivo.

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“…Both riluzole and propranolol are potent sodium channel blockers. Blocking of sodium channels by riluzole is likely involved in the clinical efficacy of the drug in amyotrophic lateral sclerosis (Benoit and Escande, 1991;Hebert et al, 1994;Song et al, 1997;Wang et al, 2008). Propranolol induces a use-dependent block of various sodium channel subtypes in a manner reminiscent of local anesthetics (Fischer, 2002;Desaphy et al, 2003;Wang et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Molecular Dissection of Lubeluzole Use–Dependent Block of Voltage-Gated Sodium Channels Discloses New Therapeutic Potentials

Desaphy

Carbonara

Costanza

et al. 2013

Molecular Pharmacology

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Lubeluzole, which acts on various targets in vitro, including voltage-gated sodium channels, was initially proposed as a neuroprotectant. The lubeluzole structure contains a benzothiazole moiety [N-methyl-1,3-benzothiazole-2-amine (R-like)] related to riluzole and a phenoxy-propranol-amine moiety [(RS)-1-(3,4-difluorophenoxy)-3-(piperidin-1-yl)propan-2-ol (A-core)] recalling propranolol. Both riluzole and propranolol are efficient sodium channel blockers. We studied in detail the effects of lubeluzole (racemic mixture and single isomers), the aforementioned lubeluzole moieties, and riluzole on sodium channels to increase our knowledge of drug-channel molecular interactions. Compounds were tested on hNav1.4 sodium channels, and on F1586C or Y1593C mutants functionally expressed in human embryonic kidney 293 cells, using the patch-clamp technique. Lubeluzole blocked sodium channels with a remarkable effectiveness. No stereoselectivity was found. Compared with mexiletine, the dissociation constant for inactivated channels was ∼600 times lower (∼11 nM), conferring to lubeluzole a huge use-dependence of great therapeutic value. The F1586C mutation only partially impaired the use-dependent block, suggesting that additional amino acids are critically involved in high-affinity binding. Lubeluzole moieties were modest sodium channel blockers. Riluzole blocked sodium channels efficiently but lacked use dependence, similar to R-like. F1586C fully abolished A-core use dependence, suggesting that A-core binds to the local anesthetic receptor. Thus, lubeluzole likely binds to the local anesthetic receptor through its phenoxy-propranol-amine moiety, with consequent use-dependent behavior. Nevertheless, compared with other known sodium channel blockers, lubeluzole adds a third pharmacophoric point through its benzothiazole moiety, which greatly enhances high-affinity binding and use-dependent block. If sufficient isoform specificity can be attained, the huge use-dependent block may help in the development of new sodium channel inhibitors to provide pharmacotherapy for membrane excitability disorders, such as myotonia, epilepsy, or chronic pain.

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Riluzole-induced block of voltage-gated Na+ current and activation of BKCa channels in cultured differentiated human skeletal muscle cells

Cited by 52 publications

References 39 publications

Activation of TREK Currents by the Neuroprotective Agent Riluzole in Mouse Sympathetic Neurons

Activation of TREK Currents by the Neuroprotective Agent Riluzole in Mouse Sympathetic Neurons

Effects of Ranolazine, a Novel Anti-anginal Drug, on Ion Currents and Membrane Potential in Pituitary Tumor GH3 Cells and NG108-15 Neuronal Cells

Molecular Dissection of Lubeluzole Use–Dependent Block of Voltage-Gated Sodium Channels Discloses New Therapeutic Potentials

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