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

John J. Crowley, Steven N. Treistman, Alejandro Dopico

Research output: Contribution to journalArticle

87 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)365-372
Number of pages8
JournalMolecular Pharmacology
Volume64
Issue number2
DOIs
StatePublished - Aug 1 2003

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Phospholipids
Ethanol
Cholesterol
Brain
Phosphatidylserines
Drug Tolerance
Membranes
Hypercholesterolemia
Alcohols

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Cholesterol antagonizes ethanol potentiation of human brain BKCa channels reconstituted into phospholipid bilayers. / Crowley, John J.; Treistman, Steven N.; Dopico, Alejandro.

In: Molecular Pharmacology, Vol. 64, No. 2, 01.08.2003, p. 365-372.

Research output: Contribution to journalArticle

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