Stimulatory effects of chlorzoxazone, a centrally acting muscle relaxant, on large conductance calcium-activated potassium channels in pituitary GH3 cells

Yen-Chin Liu, Yuk Keung Lo, Sheng-Nan Wu

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Abstract

Chlorzoxazone, a centrally acting muscle relaxant, has been used as a marker for hepatic CYP2E1 activity. However, little is known about the mechanism of chlorzoxazone actions on ion currents in neurons or neuroendocrine cells. We thus investigated its effects on ion currents in GH3 lactotrophs. Chlorzoxazone reversibly increased Ca2+-activated K+ current (IK(Ca)) in a concentration-dependent manner with an EC50 value of 30 μM. The chlorzoxazone-stimulated IK(Ca) was inhibited by iberitoxin (200 nM) or clotrimazole (10 μM), but not by glibenclamide (10 μM) or apamin (200 nM). Chlorzoxazone (30 μM) suppressed voltage-dependent L-type Ca2+ current. In the inside-out configuration, chlorzoxazone applied to the intracellular side of the patch did not modify single-channel conductance of large conductance Ca2+-activated K+ (BKCa) channels, but did increase channel activity by increasing mean open time and decreasing mean closed time. Chlorzoxazone also caused a left shift in the activation curve of BKCa channels. However, Ca2+-sensitivity of these channels was unaffected by chlorzoxazone. 1-Ethyl-2-benzimidazolinone (30 μM), 2-amino-5-chlorobenzoxazole (30 μM) or chlormezanone (30 μM) enhanced BKCa channel activity, while 6-hydroxychlorzoxazone (30 μM) slightly increased it; however, chlorphenesin carbamate (30 μM) had no effect on it. Under the current-clamp condition, chlorzoxazone (10 μM) reduced the firing rate of action potentials. In neuroblastoma IMR-32 cells, chlorzoxazone (30 μM) also stimulated BKCa channel activity. The stimulatory effects of chlorzoxazone on these channels may be responsible for the underlying mechanism of chlorzoxazone actions on neurons and neuroendocrine cells.

Original languageEnglish
Pages (from-to)86-97
Number of pages12
JournalBrain Research
Volume959
Issue number1
DOIs
Publication statusPublished - 2003 Jan 3

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Central Muscle Relaxants
Chlorzoxazone
Large-Conductance Calcium-Activated Potassium Channels
Neuroendocrine Cells
Chlormezanone
Lactotrophs
Ions
Clotrimazole
Apamin
Neurons
Calcium-Activated Potassium Channels
Cytochrome P-450 CYP2E1
Glyburide
Neuroblastoma

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

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title = "Stimulatory effects of chlorzoxazone, a centrally acting muscle relaxant, on large conductance calcium-activated potassium channels in pituitary GH3 cells",
abstract = "Chlorzoxazone, a centrally acting muscle relaxant, has been used as a marker for hepatic CYP2E1 activity. However, little is known about the mechanism of chlorzoxazone actions on ion currents in neurons or neuroendocrine cells. We thus investigated its effects on ion currents in GH3 lactotrophs. Chlorzoxazone reversibly increased Ca2+-activated K+ current (IK(Ca)) in a concentration-dependent manner with an EC50 value of 30 μM. The chlorzoxazone-stimulated IK(Ca) was inhibited by iberitoxin (200 nM) or clotrimazole (10 μM), but not by glibenclamide (10 μM) or apamin (200 nM). Chlorzoxazone (30 μM) suppressed voltage-dependent L-type Ca2+ current. In the inside-out configuration, chlorzoxazone applied to the intracellular side of the patch did not modify single-channel conductance of large conductance Ca2+-activated K+ (BKCa) channels, but did increase channel activity by increasing mean open time and decreasing mean closed time. Chlorzoxazone also caused a left shift in the activation curve of BKCa channels. However, Ca2+-sensitivity of these channels was unaffected by chlorzoxazone. 1-Ethyl-2-benzimidazolinone (30 μM), 2-amino-5-chlorobenzoxazole (30 μM) or chlormezanone (30 μM) enhanced BKCa channel activity, while 6-hydroxychlorzoxazone (30 μM) slightly increased it; however, chlorphenesin carbamate (30 μM) had no effect on it. Under the current-clamp condition, chlorzoxazone (10 μM) reduced the firing rate of action potentials. In neuroblastoma IMR-32 cells, chlorzoxazone (30 μM) also stimulated BKCa channel activity. The stimulatory effects of chlorzoxazone on these channels may be responsible for the underlying mechanism of chlorzoxazone actions on neurons and neuroendocrine cells.",
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T1 - Stimulatory effects of chlorzoxazone, a centrally acting muscle relaxant, on large conductance calcium-activated potassium channels in pituitary GH3 cells

AU - Liu, Yen-Chin

AU - Lo, Yuk Keung

AU - Wu, Sheng-Nan

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N2 - Chlorzoxazone, a centrally acting muscle relaxant, has been used as a marker for hepatic CYP2E1 activity. However, little is known about the mechanism of chlorzoxazone actions on ion currents in neurons or neuroendocrine cells. We thus investigated its effects on ion currents in GH3 lactotrophs. Chlorzoxazone reversibly increased Ca2+-activated K+ current (IK(Ca)) in a concentration-dependent manner with an EC50 value of 30 μM. The chlorzoxazone-stimulated IK(Ca) was inhibited by iberitoxin (200 nM) or clotrimazole (10 μM), but not by glibenclamide (10 μM) or apamin (200 nM). Chlorzoxazone (30 μM) suppressed voltage-dependent L-type Ca2+ current. In the inside-out configuration, chlorzoxazone applied to the intracellular side of the patch did not modify single-channel conductance of large conductance Ca2+-activated K+ (BKCa) channels, but did increase channel activity by increasing mean open time and decreasing mean closed time. Chlorzoxazone also caused a left shift in the activation curve of BKCa channels. However, Ca2+-sensitivity of these channels was unaffected by chlorzoxazone. 1-Ethyl-2-benzimidazolinone (30 μM), 2-amino-5-chlorobenzoxazole (30 μM) or chlormezanone (30 μM) enhanced BKCa channel activity, while 6-hydroxychlorzoxazone (30 μM) slightly increased it; however, chlorphenesin carbamate (30 μM) had no effect on it. Under the current-clamp condition, chlorzoxazone (10 μM) reduced the firing rate of action potentials. In neuroblastoma IMR-32 cells, chlorzoxazone (30 μM) also stimulated BKCa channel activity. The stimulatory effects of chlorzoxazone on these channels may be responsible for the underlying mechanism of chlorzoxazone actions on neurons and neuroendocrine cells.

AB - Chlorzoxazone, a centrally acting muscle relaxant, has been used as a marker for hepatic CYP2E1 activity. However, little is known about the mechanism of chlorzoxazone actions on ion currents in neurons or neuroendocrine cells. We thus investigated its effects on ion currents in GH3 lactotrophs. Chlorzoxazone reversibly increased Ca2+-activated K+ current (IK(Ca)) in a concentration-dependent manner with an EC50 value of 30 μM. The chlorzoxazone-stimulated IK(Ca) was inhibited by iberitoxin (200 nM) or clotrimazole (10 μM), but not by glibenclamide (10 μM) or apamin (200 nM). Chlorzoxazone (30 μM) suppressed voltage-dependent L-type Ca2+ current. In the inside-out configuration, chlorzoxazone applied to the intracellular side of the patch did not modify single-channel conductance of large conductance Ca2+-activated K+ (BKCa) channels, but did increase channel activity by increasing mean open time and decreasing mean closed time. Chlorzoxazone also caused a left shift in the activation curve of BKCa channels. However, Ca2+-sensitivity of these channels was unaffected by chlorzoxazone. 1-Ethyl-2-benzimidazolinone (30 μM), 2-amino-5-chlorobenzoxazole (30 μM) or chlormezanone (30 μM) enhanced BKCa channel activity, while 6-hydroxychlorzoxazone (30 μM) slightly increased it; however, chlorphenesin carbamate (30 μM) had no effect on it. Under the current-clamp condition, chlorzoxazone (10 μM) reduced the firing rate of action potentials. In neuroblastoma IMR-32 cells, chlorzoxazone (30 μM) also stimulated BKCa channel activity. The stimulatory effects of chlorzoxazone on these channels may be responsible for the underlying mechanism of chlorzoxazone actions on neurons and neuroendocrine cells.

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