BK Channel Subunit Composition Modulates Molecular Tolerance to Ethanol

Abstract

Thus, rapid tolerance in human BK occurs in cell-free membrane patches, independent of cytosolic second messengers, nucleotides or changes in free calcium. Alcohol pretreatment for 24 hours altered subsequent short-term plasticity of hSlo + beta(4) channels, suggesting a relationship between classes of tolerance. Finally, Component 2 reduction in current density showed a striking dependency on channel composition. Twenty-four hour exposure to 25 mM ethanol resulted in a down-regulation of BK current in hSlo and hSlo + beta(4) channels, but not in hSlo + beta(1) channels. The fact that hSlo + beta(1) channels show less sensitivity to acute challenge, in conjunction with less Component 1 and Component 2 tolerance, suggests subunit composition is an important factor for these elements of alcohol response.

Distinct Sensitivity of Slo1 Channel Proteins to Ethanol

“…5) (Crowley et al, 2005;Brodie et al, 2007;Feinberg-Zadek et al, 2008;Bukiya et al, 2009;Yuan et al, 2011a). Furthermore, as found for mslo1 channels (Fig.…”

“…1, A and C) (Brodie et al, 2007;Liu et al, 2008) and other slo1 channels (Crowley et al, 2005;Brodie et al, 2007;Feinberg-Zadek et al, 2008;Bukiya et al, 2009;Yuan et al, 2011a). From an structural point of view, because the slo1 region comprising the N terminus to the S0-S1 cytosolic loop is not present in slo2 (Fig.…”

“…Liu and A. Dopico, unpublished results), and with slo1 proteins cloned from human brain (hslo1) expressed in HEK cells (Feinberg-Zadek et al, 2008) or reconstituted into simple (one or two phospholipid species) bilayers (Crowley et al, 2003(Crowley et al, , 2005Yuan et al, 2011a). Such potentiation is also consistent with the 50 mM ethanolinduced decrease in macroscopic current V 0.5 observed in G/ G max -V plots (where G 5 conductance) from slo1 channels cloned from rat cerebral artery myocytes (cbv1) and expressed in X. laevis oocytes (Bukiya et al, 2009).…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Tolerance to ethanol appears in minutes as reduced channel sensitivity, followed by declustering and internalization of the channels. The b1 subunits make the BK channels insensitive to ethanol, while b4 subunits provide ethanol sensitivity (Feinberg-Zadek et al, 2008). This seems to correlate in mouse models with quicker escalation of limited access alcohol drinking after induction of dependence by chronic intermittent ethanol inhalation in the absence of the b1 subunit (Kreifeldt et al, 2013) and quicker tolerance development to motor impairment in the absence of the b4 subunit .…”

BK Channels – Focus on Polyamines, Ethanol/Acetaldehyde and Hydrogen Sulfide (H2S)

“…BK channel activity containing only the -subunit were substantially increased by ethanol, together with the 4-subunit the channel mean open time was also increased but to a lesser extent and channel activity was unaffected in the presence of 1-subunit. After prolonged ethanol exposure (24 h) down regulation of the BK current containing only hslo or hslo+ 4 was observed -but not with 1 (Feinberg-Zadek, et al 2008). Moreover, neuronal BK channels from wild-type mice expressing -and 4-subunits show little tolerance whereas BK channels from 4 knockout (KO) mice also exhibit acute tolerance to ethanol.…”