GSBS Student Publications

Title

Cholesterol antagonizes ethanol potentiation of human brain BKCa channels reconstituted into phospholipid bilayers

Student Author(s)

John J. Crowley

GSBS Program

Neuroscience

UMMS Affiliation

Department of Neurobiology; Treistman Lab; Graduate School of Biomedical Sciences, Neuroscience Program

Date

8-1-2003

Document Type

Article

Medical Subject Headings

Brain; Cholesterol; Drug Interactions; Ethanol; Humans; Large-Conductance Calcium-Activated Potassium Channels; Lipid Bilayers; Phosphatidylethanolamines; Phosphatidylserines; Phospholipids; Potassium Channels, Calcium-Activated

Disciplines

Cellular and Molecular Physiology | Molecular and Cellular Neuroscience | Molecular Biology

Abstract

The activity of large conductance, Ca2+-sensitive K+ (BKCa) channels, known to control neuronal excitability, is increased by ethanol (EtOH) exposure. Moreover, brain cholesterol (CHS) is elevated after chronic exposure to EtOH, suggesting that membrane CHS may play a role in drug tolerance. Here, we use BKCa channels from human brain (hslo subunits), reconstituted into 1-palmitoyl-2-oleoyl phosphatidylethanolamine/1-palmitoyl-2-oleoyl phosphatidylserine (POPS) bilayers, to examine CHS modulation of EtOH sensitivity. Acute exposure to clinically relevant EtOH levels increases channel activity without modifying conductance. In this minimal system, increases in CHS content within the range found in neuronal membranes lead to progressive antagonism of EtOH action. Furthermore, CHS inhibits basal channel activity with an affinity similar to that of CHS blunting of the alcohol effect. Modification of channel gating by either EtOH or CHS is reduced dramatically by removal of POPS from the bilayer, suggesting a common mechanism(s) of action. Indeed, channel dwell-time analysis indicates that CHS and EtOH exert opposite actions on the stability of channel closed states. However, each agent also acts on distinct dwell states not mirrored by the other, which contribute to the opposite effects of CHS and EtOH on channel gating.

Rights and Permissions

Citation: Mol Pharmacol. 2003 Aug;64(2):365-72. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal Title

Molecular pharmacology

PubMed ID

12869641