Abstract
Ethanol-induced inhibition of myocyte large conductance, calcium- and voltage-gated potassium (BK) current causes cerebrovascular constriction, yet the molecular targets mediating EtOH action remain unknown. Using BK channel-forming (cbv1) subunits from cerebral artery myocytes, we demonstrate that EtOH potentiates and inhibits current at Ca(i)(2+) lower and higher than approximately 15 microM, respectively. By increasing cbv1's apparent Ca(i)(2+)-sensitivity, accessory BK beta(1) subunits shift the activation-to-inhibition crossover of EtOH action to <3 microM Ca(i)(2+), with consequent inhibition of current under conditions found during myocyte contraction. Knocking-down KCNMB1 suppresses EtOH-reduction of arterial myocyte BK current and vessel diameter. Therefore, BK beta(1) is the molecular effector of alcohol-induced BK current inhibition and cerebrovascular constriction.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Calcium / metabolism
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Cerebral Arteries / cytology
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Cerebral Arteries / drug effects
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Cerebrovascular Circulation* / drug effects
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Cerebrovascular Circulation* / physiology
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Ethanol / pharmacology*
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Ion Channel Gating / drug effects
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Large-Conductance Calcium-Activated Potassium Channel beta Subunits / genetics
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Large-Conductance Calcium-Activated Potassium Channel beta Subunits / metabolism*
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Muscle Cells / cytology
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Muscle Cells / drug effects
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Muscle Cells / physiology
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Muscle, Smooth, Vascular / cytology
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Oocytes / cytology
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Oocytes / physiology
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Patch-Clamp Techniques
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Phenylephrine / pharmacology
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Rats
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Vasoconstriction / drug effects*
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Vasoconstrictor Agents / pharmacology
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Xenopus laevis
Substances
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Kcnmb1 protein, mouse
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Large-Conductance Calcium-Activated Potassium Channel beta Subunits
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Vasoconstrictor Agents
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Phenylephrine
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Ethanol
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Calcium