Beta1 (KCNMB1) subunits mediate lithocholate activation of large-conductance Ca2+-activated K+ channels and dilation in small, resistance-size arteries.
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 microM) reversibly increases the diameter of pressurized resistance cerebral arteries by approximately 10%, which would result in approximately 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-aminopyridine, 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 beta1 subunits, which are predominant in smooth muscle, are necessary for LC to modify channel activity. In contrast, beta4 subunits, which are predominant in neuronal tissues, fail to evoke LC sensitivity. LC activation of cbv1+beta1 and native BK channels display identical characteristics, including EC50 (46 microM) and Emax (approximately 300 microM) values, strongly suggesting that the cbv1+beta1 complex is necessary and sufficient to evoke LC action. Finally, intact arteries from beta1 subunit knockout mice fail to relax in response to LC, although they are able to respond to other vasodilators. This study pinpoints the BK beta1 subunit as the molecule that senses LC, which results in myocyte BK channel activation and, thus, endothelial-independent relaxation of small, resistance-size arteries.
Bukiya
Anna N
AN
Department of Pharmacology, University of Tennessee Health Science Center, 874 Union Ave. Memphis, TN 38163, USA.
Liu
Jianxi
J
Toro
Ligia
L
Dopico
Alejandro M
AM
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002536:Cerebral Arteries / Q000187:drug effects / Q000502:physiology; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects* / Q000502:physiology; D008095:Lithocholic Acid / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D021122:Protein Subunits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012503:Saponins / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology; D014655:Vascular Resistance; D014664:Vasodilation / Q000187:drug effects*
D051036:Large-Conductance Calcium-Activated Potassium Channels; D021122:Protein Subunits; D012503:Saponins; D013629:Tamoxifen; C071764:dehydrosoyasaponin I; D008095:Lithocholic Acid; D009828:Oleanolic Acid; D002118:Calcium