Blocking the actions of miR-9 with miR-9 inhibitor, or more specifically, blocking an interaction between miR-9 and 3’UTR-2.1 with microRNA target protector (Choi et al., 2007) could help to establish the consequences of miR-9 regulation of BK mRNA. However, these RNAi approaches would be unlikely to produce interpretable data. There are multiple molecular targets for miR-9 (Figure 8), some directly influencing BK gene expression or protein function, raising the possibility of a complicated and dynamic response pattern. Additionally, we have evidence for multiple forms of BK tolerance, based on several mechanisms (described below), some miR-9-independent. Therefore, in place of the RNAi approach, we used computational modeling. Although, in both, SON and striatal neurons, INSERTLESS is the most abundant transcript, while STREX and ALCOREX are less abundant, a linear extrapolation from the amounts of monomeric transcripts to the profile of the resulting channel population would be misleading. It is necessary to consider the unequal contribution of individual monomers within the tetrameric BK structure to BK channel activity and alcohol sensitivity. For example, although Insertless predominates in amount, its influence on alcohol
