β1 (KCNMB1) subunits mediate lithocholate activation of large-conductance Ca2+-activated K+ channels and dilation in small, resistance-size arteries

Anna Bukiya, Jianxi Liu, Ligia Toro, Alejandro Dopico

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Abstract

Among the nongenomic effects of steroids, control of vasomotion has received increasing attention. Lithocholate (LC) and other physiologically relevant cholane-derived steroids cause vasodilation, yet the molecular targets and mechanisms underlying this action remain largely unknown. We demonstrate that LC (45 μM) reversibly increases the diameter of pressurized resistance cerebral arteries by ∼10%, which would result in ∼30% increase in cerebral blood flow. LC action is independent of endothelial integrity, prevented by 55 nM iberiotoxin, and unmodified by 0.8 mM 4-amino-pyridine, indicating that LC causes vasodilation via myocyte BK channels. Indeed, LC activates BK channels in isolated myocytes through a destabilization of channel long-closed states without modifying unitary conductance. LC channel activation occurs within a wide voltage range and at Ca2+ concentrations reached in the myocyte at rest and during contraction. Channel accessory β1 subunits, which are predominant in smooth muscle, are necessary for LC to modify channel activity. In contrast, β4 subunits, which are predominant in neuronal tissues, fail to evoke LC sensitivity. LC activation of cbv1+β1 and native BK channels display identical characteristics, including EC50 (46 μM) and Emax (≈300 μM) values, strongly suggesting that the cbv1+β1 complex is necessary and sufficient to evoke LC action. Finally, intact arteries from β1 subunit knockout mice fail to relax in response to LC, although they are able to respond to other vasodilators. This study pinpoints the BK β1 subunit as the molecule that senses LC, which results in myocyte BK channel activation and, thus, endothelial-independent relaxation of small, resistance-size arteries.

Original languageEnglish (US)
Pages (from-to)359-369
Number of pages11
JournalMolecular Pharmacology
Volume72
Issue number2
DOIs
StatePublished - Aug 1 2007

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Lithocholic Acid
Calcium-Activated Potassium Channels
Dilatation
Arteries
Large-Conductance Calcium-Activated Potassium Channels
Muscle Cells
Vasodilation
Cholanes
Cerebrovascular Circulation
Steroids
Cerebral Arteries
Vasodilator Agents
Knockout Mice
Smooth Muscle

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

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title = "β1 (KCNMB1) subunits mediate lithocholate activation of large-conductance Ca2+-activated K+ channels and dilation in small, resistance-size arteries",
abstract = "Among the nongenomic effects of steroids, control of vasomotion has received increasing attention. Lithocholate (LC) and other physiologically relevant cholane-derived steroids cause vasodilation, yet the molecular targets and mechanisms underlying this action remain largely unknown. We demonstrate that LC (45 μM) reversibly increases the diameter of pressurized resistance cerebral arteries by ∼10{\%}, which would result in ∼30{\%} increase in cerebral blood flow. LC action is independent of endothelial integrity, prevented by 55 nM iberiotoxin, and unmodified by 0.8 mM 4-amino-pyridine, indicating that LC causes vasodilation via myocyte BK channels. Indeed, LC activates BK channels in isolated myocytes through a destabilization of channel long-closed states without modifying unitary conductance. LC channel activation occurs within a wide voltage range and at Ca2+ concentrations reached in the myocyte at rest and during contraction. Channel accessory β1 subunits, which are predominant in smooth muscle, are necessary for LC to modify channel activity. In contrast, β4 subunits, which are predominant in neuronal tissues, fail to evoke LC sensitivity. LC activation of cbv1+β1 and native BK channels display identical characteristics, including EC50 (46 μM) and Emax (≈300 μM) values, strongly suggesting that the cbv1+β1 complex is necessary and sufficient to evoke LC action. Finally, intact arteries from β1 subunit knockout mice fail to relax in response to LC, although they are able to respond to other vasodilators. This study pinpoints the BK β1 subunit as the molecule that senses LC, which results in myocyte BK channel activation and, thus, endothelial-independent relaxation of small, resistance-size arteries.",
author = "Anna Bukiya and Jianxi Liu and Ligia Toro and Alejandro Dopico",
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T1 - β1 (KCNMB1) subunits mediate lithocholate activation of large-conductance Ca2+-activated K+ channels and dilation in small, resistance-size arteries

AU - Bukiya, Anna

AU - Liu, Jianxi

AU - Toro, Ligia

AU - Dopico, Alejandro

PY - 2007/8/1

Y1 - 2007/8/1

N2 - Among the nongenomic effects of steroids, control of vasomotion has received increasing attention. Lithocholate (LC) and other physiologically relevant cholane-derived steroids cause vasodilation, yet the molecular targets and mechanisms underlying this action remain largely unknown. We demonstrate that LC (45 μM) reversibly increases the diameter of pressurized resistance cerebral arteries by ∼10%, which would result in ∼30% increase in cerebral blood flow. LC action is independent of endothelial integrity, prevented by 55 nM iberiotoxin, and unmodified by 0.8 mM 4-amino-pyridine, indicating that LC causes vasodilation via myocyte BK channels. Indeed, LC activates BK channels in isolated myocytes through a destabilization of channel long-closed states without modifying unitary conductance. LC channel activation occurs within a wide voltage range and at Ca2+ concentrations reached in the myocyte at rest and during contraction. Channel accessory β1 subunits, which are predominant in smooth muscle, are necessary for LC to modify channel activity. In contrast, β4 subunits, which are predominant in neuronal tissues, fail to evoke LC sensitivity. LC activation of cbv1+β1 and native BK channels display identical characteristics, including EC50 (46 μM) and Emax (≈300 μM) values, strongly suggesting that the cbv1+β1 complex is necessary and sufficient to evoke LC action. Finally, intact arteries from β1 subunit knockout mice fail to relax in response to LC, although they are able to respond to other vasodilators. This study pinpoints the BK β1 subunit as the molecule that senses LC, which results in myocyte BK channel activation and, thus, endothelial-independent relaxation of small, resistance-size arteries.

AB - Among the nongenomic effects of steroids, control of vasomotion has received increasing attention. Lithocholate (LC) and other physiologically relevant cholane-derived steroids cause vasodilation, yet the molecular targets and mechanisms underlying this action remain largely unknown. We demonstrate that LC (45 μM) reversibly increases the diameter of pressurized resistance cerebral arteries by ∼10%, which would result in ∼30% increase in cerebral blood flow. LC action is independent of endothelial integrity, prevented by 55 nM iberiotoxin, and unmodified by 0.8 mM 4-amino-pyridine, indicating that LC causes vasodilation via myocyte BK channels. Indeed, LC activates BK channels in isolated myocytes through a destabilization of channel long-closed states without modifying unitary conductance. LC channel activation occurs within a wide voltage range and at Ca2+ concentrations reached in the myocyte at rest and during contraction. Channel accessory β1 subunits, which are predominant in smooth muscle, are necessary for LC to modify channel activity. In contrast, β4 subunits, which are predominant in neuronal tissues, fail to evoke LC sensitivity. LC activation of cbv1+β1 and native BK channels display identical characteristics, including EC50 (46 μM) and Emax (≈300 μM) values, strongly suggesting that the cbv1+β1 complex is necessary and sufficient to evoke LC action. Finally, intact arteries from β1 subunit knockout mice fail to relax in response to LC, although they are able to respond to other vasodilators. This study pinpoints the BK β1 subunit as the molecule that senses LC, which results in myocyte BK channel activation and, thus, endothelial-independent relaxation of small, resistance-size arteries.

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