title: Modulation of recombinant small-conductance Ca(2+)-activated K(+) channels by the muscle relaxant chlorzoxazone and structurally related compounds.
abstract: Using the patch clamp technique we investigated the effects of the centrally acting muscle relaxant chlorzoxazone and three structurally related compounds, 1-ethyl-2-benzimidazolinone (1-EBIO), zoxazolamine, and 1,3-dihydro-1-[2-hydroxy-5-(triflu oromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one (NS 1619) on recombinant rat brain SK2 channels (rSK2 channels) expressed in HEK293 mammalian cells. SK channels are small conductance K(+) channels normally activated by a rise in intracellular Ca(2+) concentration; they modulate the electrical excitability in neurons and neuroendocrine cells. When applied externally, chlorzoxazone, 1-EBIO, and zoxazolamine activated rSK2 channel currents in cells dialyzed with a nominally Ca(2+)-free intracellular solution. The activation was reversible, reproducible, and depended on the chemical structure and concentration. The order of potency was 1-EBIO > chlorzoxazone > zoxazolamine. Activation of rSK2 channels by chlorzoxazone, 1-EBIO, and zoxazolamine declined at higher drug concentrations. Zoxazolamine, when applied in combination with chlorzoxazone or 1-EBIO, partially inhibited the rSK2 channel current responses, suggesting a partial-agonist mode of action. 1-EBIO failed to activate rSK2 channel currents when applied to excised inside-out membrane patches exposed to a Ca(2+)-free intracellular solution. In contrast, 1-EBIO activated rSK2 currents in a concentration-dependent manner when coapplied to the patches with a solution containing 20 nM free Ca(2+). NS 1619 did not activate rSK2 channel currents; it inhibited rSK2 channel currents activated by the other three test compounds or by high intracellular Ca(2+). We conclude that chlorzoxazone and its derivatives act through a common mechanism to modulate rSK2 channels, and SK channel modulation in the brain may partly underlie the clinical effects of chlorzoxazone.
authors.affiliation: Department of Anesthesia and Critical Care, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Cao
authors.forename: J C
authors.initials: JC
authors.lastname: Dreixler
authors.forename: J D
authors.initials: JD
authors.lastname: Roizen
authors.forename: M T
authors.initials: MT
authors.lastname: Roberts
authors.forename: K M
authors.initials: KM
authors.lastname: Houamed
mesh_terms: D001562:Benzimidazoles / Q000494:pharmacology; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002478:Cells, Cultured; D002753:Chlorzoxazone / Q000737:chemistry / Q000494:pharmacology*; D004594:Electrophysiology; D006801:Humans; D009125:Muscle Relaxants, Central / Q000737:chemistry / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D024681:Potassium Channels, Calcium-Activated; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D051640:Small-Conductance Calcium-Activated Potassium Channels; D013329:Structure-Activity Relationship; D015049:Zoxazolamine / Q000494:pharmacology
chemical_list: D001562:Benzimidazoles; D002120:Calcium Channel Agonists; C496897:KCNN2 protein, human; D009125:Muscle Relaxants, Central; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D011994:Recombinant Proteins; D051640:Small-Conductance Calcium-Activated Potassium Channels; C086491:NS 1619; D015049:Zoxazolamine; D002753:Chlorzoxazone; C102635:1-ethyl-2-benzimidazolinone