Brudnick Neuropsychiatric Research Institute, Department of Psychiatry; Martin Lab
Biochemical Phenomena, Metabolism, and Nutrition | Biochemistry, Biophysics, and Structural Biology | Chemical and Pharmacologic Phenomena | Neuroscience and Neurobiology
Tolerance is a well described component of alcohol abuse and addiction. The large conductance voltage- and Ca(2+)-gated potassium channel (BK) has been very useful for studying molecular tolerance. The influence of association with the beta4 subunit can be observed at the level of individual channels, action potentials in brain slices, and finally, drinking behavior in the mouse. Previously, we showed that 50 mm alcohol increases both alpha and alphabeta4 BK channel open probability, but only alpha BK develops acute tolerance to this effect. Currently, we explore the possibility that the influence of the beta4 subunit on tolerance may result from a striking effect of beta4 on kinase modulation of the BK channel. We examine the influence of the beta4 subunit on PKA, CaMKII, and phosphatase modulation of channel activity, and on molecular tolerance to alcohol. We record from human BK channels heterologously expressed in HEK 293 cells composed of its core subunit, alpha alone (Insertless), or co-expressed with the beta4 BK auxiliary subunit, as well as, acutely dissociated nucleus accumbens neurons using the cell-attached patch clamp configuration. Our results indicate that BK channels are strongly modulated by activation of specific kinases (PKA and CaMKII) and phosphatases. The presence of the beta4 subunit greatly influences this modulation, allowing a variety of outcomes for BK channel activity in response to acute alcohol.
Alcohol, Neuron, Phosphorylation, Potassium Channel, Tolerance
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© 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Publisher PDF posted after 12 months as allowed by the publisher's author rights policy at http://www.jbc.org/site/misc/License%20to%20Publish_author%20retains%20ownership_v1_JBC.pdf.
DOI of Published Version
J Biol Chem. 2014 Oct 17;289(42):29261-72. doi: 10.1074/jbc.M114.604306. Epub 2014 Sep 4. Link to article on publisher's site
The Journal of biological chemistry
Velazquez-Marrero, Cristina; Seale, Garrett E.; Treistman, Steven N.; and Martin, Gilles E., "Large conductance voltage- and Ca2+-gated potassium (BK) channel beta4 subunit influences sensitivity and tolerance to alcohol by altering its response to kinases" (2014). University of Massachusetts Medical School Faculty Publications. 1458.