Acute alcohol tolerance is intrinsic to the BKCa protein, but is modulated by the lipid environment
Authors
Yuan, ChunboO'Connell, Robert J.
Wilson, Andrew H.
Pietrzykowski, Andrzej Z.
Treistman, Steven N.
UMass Chan Affiliations
Treistman LabDepartment of Psychiatry
Brudnick Neuropsychiatric Research Institute
Document Type
Journal ArticlePublication Date
2007-12-18Keywords
Alcohol-Related DisordersAnimals
Behavior, Animal
Caenorhabditis elegans
Cell Line
Central Nervous System Depressants
Drug Synergism
Drug Tolerance
Ethanol
Humans
Large-Conductance Calcium-Activated Potassium Channel alpha
Subunits
Membrane Lipids
Neurons
Life Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
Ethanol tolerance, in which exposure leads to reduced sensitivity, is an important component of alcohol abuse and addiction. The molecular mechanisms underlying this process remain poorly understood. The BKCa channel plays a central role in the behavioral response to ethanol in Caenorhabditis elegans (Davies, A. G., Pierce-Shimomura, J. T., Kim, H., VanHoven, M. K., Thiele, T. R., Bonci, A., Bargmann, C. I., and McIntire, S. L. (2003) Cell 115, 655-666) and Drosophila (Cowmeadow, R. B., Krishnan, H. R., and Atkinson, N. S. (2005) Alcohol. Clin. Exp. Res. 29, 1777-1786) . In neurons, ethanol tolerance in BKCa channels has two components: a reduced number of membrane channels and decreased potentiation of the remaining channels (Pietrzykowski, A. Z., Martin, G. E., Puig, S. I., Knott, T. K., Lemos, J. R., and Treistman, S. N. (2004) J. Neurosci. 24, 8322-8332) . Here, heterologous expression coupled with planar bilayer techniques examines two additional aspects of tolerance in human BKCa channels. 1) Is acute tolerance observed in a single channel protein complex within a lipid environment reduced to only two lipids? 2) Does lipid bilayer composition affect the appearance of acute tolerance? We found that tolerance was observable in BKCa channels in membrane patches pulled from HEK cells and when they are placed into reconstituted 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylethanolamine/1-palmitoyl-2-o leoyl-sn-glycero-3-phosphatidylserine membranes. Furthermore, altering bilayer thickness by incorporating the channel into lipid mixtures of 1,2-dioleoyl-3-phosphatidylethanolamine with phosphatidylcholines of increasing chain length, or with sphingomyelin, strongly affected the sensitivity of the channel, as well as the time course of the acute response. Ethanol sensitivity changed from a strong potentiation in thin bilayers to inhibition in thick sphingomyelin/1,2-dioleoyl-3-phosphatidylethanolamine bilayers. Thus, tolerance can be an intrinsic property of the channel protein-lipid complex, and bilayer thickness plays an important role in shaping the pattern of response to ethanol. As a consequence of these findings the protein-lipid complex should be treated as a unit when studying ethanol action.Source
J Biol Chem. 2008 Feb 22;283(8):5090-8. Epub 2007 Dec 15. Link to article on publisher's siteDOI
10.1074/jbc.M708214200Permanent Link to this Item
http://hdl.handle.net/20.500.14038/39265PubMed ID
18084004Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1074/jbc.M708214200