Ethanol Effect on BK Channels is Modulated by Magnesium.

Abstract

Alcoholics have been reported to have reduced levels of magnesium in both their extracellular and intracellular compartments. Calcium-dependent potassium channels (BK) are known to be one of ethanol (EtOH)'s better known molecular targets. Using outside-out patches from hippocampal neuronal cultures, we examined the consequences of altered intracellular Mg(2+) on the effects that EtOH has on BK channels. We find that the effect of EtOH is bimodally influenced by the Mg(2+) concentration on the cytoplasmic side. More specifically, when internal Mg(2+) concentrations are ≤200 μM, EtOH decreases BK activity, whereas it increases activity when Mg(2+) is at 1 mM. Similar results are obtained when using patches from HEK cells expressing only the α-subunit of BK. When patches are made with the actin destabilizer cytochalasin D present on the cytoplasmic side, the potentiation caused by EtOH becomes independent of the Mg(2+) concentration. Furthermore, in the presence of the actin stabilizer phalloidin, EtOH causes inhibition even at Mg(2+) concentrations of 1 mM. Internal Mg(2+) can modulate the EtOH effects on BK channels only when there is an intact, internal actin interaction with the channel, as is found at synapses. We propose that the EtOH-induced decrease in cytoplasmic Mg(2+) observed in frequent/chronic drinkers would decrease EtOH's actions on synaptic (e.g., actin-bound) BK channels, producing a form of molecular tolerance.