Here, we describe a mechanism of alcohol tolerance involving miRNA. Clinically relevant alcohol concentrations rapidly increase miR-9 levels in central neurons. Only one out of three BK channel 3’UTRs contains a MRE with complementarity to miR-9. Thus, there is a selective degradation of message, resulting in reorganization of BK splice variant profile. Modeling, based upon experimental results indicating the baseline levels of the various transcripts, combined with the differential downregulation of BK transcripts by alcohol, allowed a determination of the post-exposure distribution of tetrameric channels. Further, when the model included data (obtained from expression studies) describing differential alcohol responsiveness within this channel population, the resulting prediction was consistent with the development of tolerance. We show also that alcohol, via miR-9 upregulation, regulates additional targets, suggesting a central role for miR-9 in alcohol’s actions in the CNS.
