The BK channel accessory beta1 subunit determines alcohol-induced cerebrovascular constriction.
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.
Bukiya
Anna N
AN
The University of Tennessee Health Science Center, College of Medicine, Department of Pharmacology, Memphis, TN 38163, USA.
Liu
Jianxi
J
Dopico
Alejandro M
AM
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002536:Cerebral Arteries / Q000166:cytology / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D000431:Ethanol / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032342:Muscle Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D009865:Oocytes / Q000166:cytology / Q000502:physiology; D018408:Patch-Clamp Techniques; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014982:Xenopus laevis
C543091:Kcnmb1 protein, mouse; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D000431:Ethanol; D002118:Calcium