title: Smooth muscle cholesterol enables BK β1 subunit-mediated channel inhibition and subsequent vasoconstriction evoked by alcohol.
abstract: OBJECTIVE
  Hypercholesterolemia and alcohol drinking constitute independent risk factors for cerebrovascular disease. Alcohol constricts cerebral arteries in several species, including humans. This action results from inhibition of voltage- and calcium-gated potassium channels (BK) in vascular smooth muscle cells (VSMC). BK activity is also modulated by membrane cholesterol. We investigated whether VSMC cholesterol regulates ethanol actions on BK and cerebral arteries.
  
  
  RESULTS
  After myogenic tone development, cholesterol depletion of rat, resistance-size cerebral arteries ablated ethanol-induced constriction, a result that was identical in intact and endothelium-free vessels. Cholesterol depletion reduced ethanol inhibition of BK whether the channel was studied in VSMC or after rat cerebral artery myocyte subunit (cbv1+β1) reconstitution into phospholipid bilayers. Homomeric cbv1 channels reconstituted into bilayers and VSMC BK from β1 knockout mice were both resistant to ethanol-induced inhibition. Moreover, arteries from β1 knockout mice failed to respond to ethanol even when VSMC cholesterol was kept unmodified. Remarkably, ethanol inhibition of cbv1+β1 in bilayers and wt mouse VSMC BK were drastically blunted by cholesterol depletion. Consistently, cholesterol depletion suppressed ethanol constriction of wt mouse arteries.
  
  
  CONCLUSIONS
  VSMC cholesterol and BK β1 are both required for ethanol inhibition of BK and the resulting cerebral artery constriction, with health-related implications for manipulating cholesterol levels in alcohol-induced cerebrovascular disease.
authors.affiliation: University of Tennessee Health Science Center, Department of Pharmacology, Memphis, TN 38163, USA. abukiya@uthsc.edu
authors.forename: Anna N
authors.initials: AN
authors.lastname: Bukiya
authors.forename: Thirumalini
authors.initials: T
authors.lastname: Vaithianathan
authors.forename: Guruprasad
authors.initials: G
authors.lastname: Kuntamallappanavar
authors.forename: Maria
authors.initials: M
authors.lastname: Asuncion-Chin
authors.forename: Alex M
authors.initials: AM
authors.lastname: Dopico
mesh_terms: D000818:Animals; D002536:Cerebral Arteries / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D002784:Cholesterol / Q000378:metabolism*; D004594:Electrophysiology / Q000379:methods; D000431:Ethanol / Q000009:adverse effects / Q000494:pharmacology*; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008051:Lipid Bilayers / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology
chemical_list: D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008051:Lipid Bilayers; D000431:Ethanol; D002784:Cholesterol