Large conductance voltage- and Ca2+-gated potassium (BK) channel ?4 subunit influences sensitivity and tolerance to alcohol by altering its response to kinases.

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 ?4 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 ? and ??4 BK channel open probability, but only ? BK develops acute tolerance to this effect. Currently, we explore the possibility that the influence of the ?4 subunit on tolerance may result from a striking effect of ?4 on kinase modulation of the BK channel. We examine the influence of the ?4 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, ? alone (Insertless), or co-expressed with the ?4 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 ?4 subunit greatly influences this modulation, allowing a variety of outcomes for BK channel activity in response to acute alcohol.

SUBMITTER: Velazquez-Marrero C 

PROVIDER: S-EPMC4200277 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature