title: Type 2 ryanodine receptors are highly sensitive to alcohol.
abstract: Exposure to ethanol levels reached in circulation during alcohol intoxication (>10mM) constricts cerebral arteries in rats and humans. Remarkably, targets and mechanisms underlying this action remain largely unidentified. Artery diameter is regulated by myocyte Ca(2+) sparks, a vasodilatory signal contributed to by type 2 ryanodine receptors (RyR2). Using laser confocal microscopy in rat cerebral arteries and bilayer electrophysiology we unveil that ethanol inhibits both Ca(2+) spark and RyR2 activity with IC50<20 mM, placing RyR2 among the ion channels that are most sensitive to ethanol. Alcohol directly targets RyR2 and its lipid microenvironment, leading to stabilization of RyR2 closed states.
authors.affiliation: Department of Pharmacology, The University of Tennessee Health Science Center, Memphis, TN 38163, United States.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Department of Pharmacology, The University of Tennessee Health Science Center, Memphis, TN 38163, United States.
authors.forename: Kuihuan
authors.initials: K
authors.lastname: Jian
authors.affiliation: Department of Physiology, The University of Tennessee Health Science Center, Memphis, TN 38163, United States.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Jaggar
authors.affiliation: Department of Pharmacology, The University of Tennessee Health Science Center, Memphis, TN 38163, United States.
authors.forename: Anna N
authors.initials: AN
authors.lastname: Bukiya
authors.affiliation: Department of Pharmacology, The University of Tennessee Health Science Center, Memphis, TN 38163, United States. Electronic address: adopico@uthsc.edu.
authors.forename: Alex M
authors.initials: AM
authors.lastname: Dopico
mesh_terms: D000435:Alcoholic Intoxication / Q000503:physiopathology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects*; D002492:Central Nervous System Depressants / Q000494:pharmacology; D002536:Cerebral Arteries / Q000187:drug effects / Q000503:physiopathology; D000431:Ethanol / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D055550:Protein Stability; D051381:Rats; D017207:Rats, Sprague-Dawley; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*
chemical_list: D002121:Calcium Channel Blockers; D002492:Central Nervous System Depressants; D019837:Ryanodine Receptor Calcium Release Channel; D000431:Ethanol
keywords: Alcohol; Cerebral artery smooth muscle; Lipid bilayer electrophysiology; Ryanodine receptor