Adaptation of BK to alcohol (molecular tolerance) involves both reduced sensitivity to the drug after exposure, which occurs within minutes, and a slower-developing declustering within groups of channels and subsequent internalization of channels from the plasma membrane (leading to decreased current density), measured in hours [39]. After 24-h exposure, BK channels remaining in the membrane are (i) less potentiated by acute challenge; (ii) less clustered; and (iii) less dense within remaining clusters [10]. Overall, the “tolerant” BK population exhibits a higher proportion of internalized channels [10] (Figure 2). The nature of the alcohol–BK interaction is significantly more direct and specific than would have been predicted from prevalent belief several years ago. Much of the initial work establishing the nature of the alcohol–BK interaction was performed in the hypothalamic–neurohypophysial system [responsible for release of the neuropeptides vasopressin (AVP) and oxytocin (OT)] and includes: Establishment of L-type Ca channels and BK channels in neurohypophysial terminals as targets of acute ethanol action, associated with the inhibition of peptide hormone release from these terminals.Discovery that gating is the attribute in both L-type Ca channels
