Acute exposure of cerebral arteries to alcohol (as in binge drinking) is known to cause cerebral vasospasm and stroke. The risk for this pathology is increased by mechanisms that impair cerebral vasodilation, such as high cholesterol Most of the evidence indicates that alcohol-induced cerebral artery constriction is due to a direct contraction of cerebral smooth muscle by ethanol (EtOH). However, the ionic mechanisms that determine EtOH-induced cerebrovascular contraction are unknown. Large conductance, Ca++-activated K + (BK) channel activity in the cerebral artery smooth muscle critically limits the degree of contraction. BK channels consist of alpha (encoded by the slo gene) and beta subunits. Slo expression renders currents that bear all the key features of BK channels. The ultimate goal of this application is to identify the molecular factors and mechanisms determining EtOH modulation of cerebrovascular BK channel activity and the contribution of this modulation to cerebrovascular smooth muscle contraction induced by acute EtOH. Based on our previous data, we have narrowed down the molecular entities determining a particular BK channel response to acute EtOH exposure to: 1) the particular slo channel isoform; and 2) the lipid (in particular, steroid) environment of the slo subunit. Therefore, using a combination of pharmacological, electrophysiological (patch-clamp) and Molecular Biology techniques, here we will comprehensively address EtOH modulation of BK channel function in cerebrovascular smooth muscle by sequentially examining drug action in: 1) the isolated cerebral artery to determine the contribution of EtOH modulation of BK channel function to alcohol action on cerebral artery constriction; 2) isolated cerebrovascular myocytes to address a direct EtOH-BK channel complex interaction when the channel is embedded in its natural membrane environment and, taken advantage of our recent cloning of slo from cerebral artery myocytes, 3) model systems to probe a direct slo subunit-EtOH interaction and establish its molecular determinants, including modulation by membrane steroids. Pinpointing the molecular mechanisms involved in EtOH action on cerebrovascular BK channels will bring fundamental information for the rationale design of drugs of potential therapeutic use in alcohol-induced cerebrovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA011560-09
Application #
7029626
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Brown, Ricardo A
Project Start
1999-01-01
Project End
2009-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
9
Fiscal Year
2006
Total Cost
$288,508
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Bukiya, Anna N; Dopico, Alex M (2018) Fetal Cerebral Circulation as Target of Maternal Alcohol Consumption. Alcohol Clin Exp Res 42:1006-1018
Kuntamallappanavar, Guruprasad; Bisen, Shivantika; Bukiya, Anna N et al. (2017) Differential distribution and functional impact of BK channel beta1 subunits across mesenteric, coronary, and different cerebral arteries of the rat. Pflugers Arch 469:263-277
Bukiya, Anna N; McMillan, Jacob; Liu, Jianxi et al. (2014) Activation of calcium- and voltage-gated potassium channels of large conductance by leukotriene B4. J Biol Chem 289:35314-25
Bukiya, Anna; Dopico, Alejandro M; Leffler, Charles W et al. (2014) Dietary cholesterol protects against alcohol-induced cerebral artery constriction. Alcohol Clin Exp Res 38:1216-26
Bukiya, Anna N; McMillan, Jacob E; Fedinec, Alexander L et al. (2013) Cerebrovascular dilation via selective targeting of the cholane steroid-recognition site in the BK channel ?1-subunit by a novel nonsteroidal agent. Mol Pharmacol 83:1030-44
Bukiya, Anna N; Belani, Jitendra D; Rychnovsky, Scott et al. (2011) Specificity of cholesterol and analogs to modulate BK channels points to direct sterol-channel protein interactions. J Gen Physiol 137:93-110
Vaithianathan, Thirumalini; Narayanan, Damodaran; Asuncion-Chin, Maria T et al. (2010) Subtype identification and functional characterization of ryanodine receptors in rat cerebral artery myocytes. Am J Physiol Cell Physiol 299:C264-78
Cheng, Xiaoyang; Pachuau, Judith; Blaskova, Eva et al. (2009) Alternative splicing of Cav1.2 channel exons in smooth muscle cells of resistance-size arteries generates currents with unique electrophysiological properties. Am J Physiol Heart Circ Physiol 297:H680-8
Mulholland, Patrick J; Hopf, F Woodward; Bukiya, Anna N et al. (2009) Sizing up ethanol-induced plasticity: the role of small and large conductance calcium-activated potassium channels. Alcohol Clin Exp Res 33:1125-35
Dopico, Alex M; Lovinger, David M (2009) Acute alcohol action and desensitization of ligand-gated ion channels. Pharmacol Rev 61:98-114

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