University of Massachusetts Medical School Faculty Publications

UMMS Affiliation

Brudnick Neuropsychiatric Research Institute, Department of Psychiatry; Martin Lab

Publication Date

2014-10-17

Document Type

Article

Disciplines

Biochemical Phenomena, Metabolism, and Nutrition | Biochemistry, Biophysics, and Structural Biology | Chemical and Pharmacologic Phenomena | Neuroscience and Neurobiology

Abstract

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.

Keywords

Alcohol, Neuron, Phosphorylation, Potassium Channel, Tolerance

Rights and Permissions

© 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

10.1074/jbc.M114.604306

Source

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

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

The Journal of biological chemistry

PubMed ID

25190810

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