In addition to the route for adaptation provided by post-transcriptional regulation of ion channel mRNA stability by miR-9, other cellular mechanisms contribute to the development of BK alcohol tolerance. Alcohol tolerance is a complex phenomenon and has several forms, e.g. acute, rapid, or chronic tolerance, depending upon the length of alcohol exposure and the consequent involvement of cellular mechanisms. Our working hypothesis is that acute tolerance occurs via posttranslational effects of the drug directly on the existing channel, which allow rapid alterations that are relatively short-lived. In contrast, longer forms of tolerance can be attributable to other mechanisms acting up-stream of posttranslational changes. They include post-transcriptional regulation of stability of existing transcripts (e.g. via miR-9), followed by protein synthesis and insertion of new functional channels into the plasma membrane. These post-transcriptional mechanisms may result in a slower-developing, but longer-lived adaptation to alcohol exposure. Thus, although the effects of alcohol on upregulation of miR-9 and subsequent subtractive rearrangement of the BK mRNA isoform landscape are surprisingly fast, the functional consequences will be delayed, dependent upon translation of the message, and subsequent delivery and insertion of the channel protein into the neuronal plasma membrane.
