Alcohol modulation of BK channel gating depends on β subunit composition

Abstract

Large conductance K+ channels of the slo1 family are gated by Ca2+ and voltage and either inhibited or potentiated by ethanol. Kuntamallappanavar and Dopico analyze the effects of ethanol in detail and find that the absence or presence of β subunits leads to differential modification of channel gating parameters by intoxicating levels of ethanol.

Statin therapy exacerbates alcohol-induced constriction of cerebral arteries via modulation of ethanol-induced BK channel inhibition in vascular smooth muscle

“…Therefore, atorvastatin treatment resulted in decreased BK channel activity as more membrane depolarization was needed to reach half-maximal BK current when compared to placebo. The result is consistent with a diminished functionality of BK channel beta1 subunits [6,38]. Thus, while atorvastatin exacerbates ethanol-induced BK channel inhibition, statin treatment diminishes basal channel function.…”

Differential distribution and functional impact of BK channel beta1 subunits across mesenteric, coronary, and different cerebral arteries of the rat

“…Furthermore, the parallel leftward shift in the NP o /NP o max -V curve seen at physiological Ca 2+ i is consistent with an increased presence of functional BK β1 subunits [5,11,27,50,51,67,70]. Interestingly, the actual BK V half values in myocytes from BA and CA are similar to those found using heterologous expression systems in which overexpression of β1 subunits is considered to saturate their slo1 partners, including slo1 cloned from rat cerebral artery myocytes ([5,11,27,50,51,70]; e.g., at physiological 3 μM Ca 2+ i , V half values for BA, CA, and slo1+β1 overexpressed in oocytes are 23.5±5.9, 25.15±3.4 and 24.7 ± 13.0 [27]), respectively. Collectively, our electrophysiological data strongly suggest that the increased activity of myocyte BK channels in CA and BA is primarily due to an increased functional presence of BK β1 in these arteries.…”

“…On the other hand, it is widely accepted that within physiological levels of Ca 2+ i and voltage, over-expression of β1 subunits with slo1 in heterologous systems (HEK293 cells, X. laevis oocytes) leads to increased BK steady-state activity [5,11,27,50,51]. The stoichiometry of slo1 and β1 subunits in native channels across different vascular and nonvascular tissues remains largely unknown.…”

BK β1 subunit‐dependent facilitation of ethanol inhibition of BK current and cerebral artery constriction is mediated by the β1 transmembrane domain 2

“…Four β types have been identified (encoded by KCNMB1–4 ), with β1 prevailing in smooth muscle and β4 prevailing in neurons (Brenner et al, ). Remarkably, β1 subunits are required for ethanol to inhibit cerebral artery myocyte BK channels at Ca 2+ i > 2 μM and across a wide voltage range (Bukiya et al, ,b; Kuntamallappanavar and Dopico, ). These conditions include the levels of Ca 2+ i (~4–30 μM) faced by the BK channel that result from depolarization (−40 mV)‐induced Ca 2+ ‐entry and from internal Ca 2+ ‐release via ryanodine receptor‐mediated Ca 2+ sparks.…”

“…Under these conditions, β1‐containing BK channels negatively feedback on depolarization‐induced Ca 2+ i entry and on cerebral artery constriction (Pérez et al, ). In contrast, β4‐subunits do not support ethanol inhibitory action (Feinberg‐Zadek et al, ; Martin et al, ; Kuntamallappanavar and Dopico, ). All the different β1 regions contribute to the ionic current phenotype of slo1 + β1 channels (Gruslova et al, ; Kuntamallappanavar et al, ; Castillo et al, ).…”