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High-conductance, Ca(2+)-activated and voltage-gated (BK) channels set neuronal firing. They are almost universally activated by alcohol, leading to reduced neuronal excitability and neuropeptide release and to motor intoxication. However, several BK channels are inhibited by alcohol, and most other voltage-gated K(+) channels are refractory to drug action. BK channels are homotetramers (encoded by Slo1) that possess a unique transmembrane segment (S0), leading to a cytosolic S0-S1 loop. We identified Thr107 of bovine slo (bslo) in this loop as a critical residue that determines BK channel responses to alcohol. In addition, the activity of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in the cell controlled channel activity and alcohol modulation. Incremental CaMKII-mediated phosphorylation of Thr107 in the BK tetramer progressively increased channel activity and gradually switched the channel alcohol responses from robust activation to inhibition. Thus, CaMKII phosphorylation of slo Thr107 works as a 'molecular dimmer switch' that could mediate tolerance to alcohol, a form of neuronal plasticity.
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