Effects of Lipid Composition and Alcohol on BK Channel Function.
The Treistman laboratory is generally interested in exploring the mechanisms which underlie the ability of physiological doses of alcohol to alter the functional properties of neurons in the brain. Although changes in lipid membrane properties were long thought to be responsible for the reduction in neuronal excitability generally observed with application of this drug, we have recently demonstrated that alcohol also has direct effects on the transmembrane BKCa channel protein that is responsible for potassium current flow across nerve membranes. This channel is a key player in determining the excitability of neurons in which it is found. The functional properties of the lipids and proteins forming neuronal membranes are inextricably intertwined so that it is unlikely that a particular drug will fail to interact with both substrates. Accordingly, our specific research interest centers on dissecting the effects of altering the membrane lipid composition on the electrophysiological properties of the BKCa channel. Each channel is reconstituted into a lipid bilayer of known composition. As we vary lipid composition, we next hope to determine how the application of alcohol alters channel function. At the moment we find first that rather large alterations in BKCa channel conductance and activation occur with changes in lipid composition. On top of this, preliminary experiments now show that alcohol's effect on BKCa channel properties can be further altered by simply changing lipid composition. We hope to determine the physical properties of the bilayer that are responsible for these effects. We have also recently demonstrated that BKCa channel properties show alterations in response that are reminiscent of tolerance to alcohol in the whole organism. This suggests that drugs that target protein channels may have therapeutic effects in treating alcohol addiction.
Publications
Yuan,C., R.J.O'Connell, P.L.Feinberg-Zadek, L.J.Johnston, and S.N.Treistman. 2004. Bilayer thickness modulates the conductance of the BK channel in model membranes. Biophys. J. 86:3620-3633.
