Cholesterol Tuning of BK Ethanol Response Is Enantioselective, and Is a Function of Accompanying Lipids

Yuan, Changxia; Chen, Maohui; Covey, Douglas F.; Johnston, Linda J.; Treistman, Steven N.

doi:10.1371/journal.pone.0027572

Cited by 32 publications

(40 citation statements)

References 61 publications

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“…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.…”

Section: Discussionsupporting

confidence: 66%

“…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.…”

Section: Resultsmentioning

confidence: 99%

“…Liu and A. Dopico, unpublished results), and with slo1 proteins cloned from human brain (hslo1) expressed in HEK cells (Feinberg-Zadek et al, 2008) or reconstituted into simple (one or two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).…”

Section: Discussionmentioning

confidence: 98%

“…It has been shown that the final ethanol effect on BK NPo results from the orchestration of several factors, including the phosphorylation of the channel-forming slo1 subunit (Liu et al, 2006), the presence of channel accessory proteins Bukiya et al, 2009;Wynne et al, 2009), the cholesterol amount in the membrane where the channel resides (Crowley et al, 2003;Bukiya et al, 2011;Yuan et al, 2011a), and the type of phospholipid species in the lipid membrane (Crowley et al, 2005;Yuan et al, 2011a). However, work from reductionist systems has demonstrated that ethanol action on BK channels requires a minimum set of targets: the slo1 subunit and a one-or two-species phospholipid bilayer (Crowley et al, 2005;Brodie et al, 2007;Yuan et al, 2011a).…”

Section: Introductionmentioning

confidence: 99%

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Distinct Sensitivity of Slo1 Channel Proteins to Ethanol

et al. 2012

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Ethanol levels reached in circulation during moderate-to-heavy alcohol intoxication (50-100 mM) modify Ca 21 -and voltagegated K 1 (BK) channel steady-state activity, eventually altering both physiology and behavior. Ethanol action on BK steadystate activity solely requires the channel-forming subunit slo1 within a bare lipid environment. To identify the protein regions that confer ethanol sensitivity to slo1, we tested the ethanol sensitivity of heterologously expressed slo1 and structurally related channels. Ethanol (50 mM) increased the steady-state activities of mslo1 and Ca 21 -gated MthK, the latter after channel reconstitution into phospholipid bilayers. In contrast, 50-100 mM ethanol failed to alter the steady-state activities of Na 1 /Cl 2 -gated rslo2, H 1 -gated mslo3, and an mslo1/3 chimera engineered by joining the mslo1 region encompassing the N terminus to S6 with the mslo3 cytosolic tail domain (CTD). Collectively, data indicate that the slo family canonical design, which combines a transmembrane 6 (TM6) voltage-gated K 1 channel (K V ) core with CTDs that empower the channel with ion-sensing, does not necessarily render ethanol sensitivity. In addition, the region encompassing the N terminus to the S0-S1 cytosolic loop (missing in MthK) is not necessary for ethanol action. Moreover, incorporation of both this region and an ionsensing CTD to TM6 K V cores (a design common to mslo1, mslo3, and the mslo1/mslo3 chimera) is not sufficient for ethanol sensitivity. Rather, a CTD containing Ca 21 -sensing regulator of conductance for K 1 domains seems to be critical to bestow K V structures, whether of TM2 (MthK) or TM6 (slo1), with sensitivity to intoxicating ethanol levels.

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“…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.…”

Section: Discussionsupporting

confidence: 66%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Distinct Sensitivity of Slo1 Channel Proteins to Ethanol

et al. 2012

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“…Ent -cholesterol is a “mirror image” of natural cholesterol, with both compounds sharing major physicochemical properties. Because cholesterol chirality has a minor effect on protein-free phospholipid media [15], differential effects of cholesterol vs. ent -cholesterol have been widely used as a criterion to establish that cholesterol modification of membrane protein function is the result of cholesterol recognition by a specific protein site(s) [16–19]. Ent -cholesterol enrichment of rat middle cerebral arteries was performed and verified following the protocol used for enrichment with natural cholesterol (Fig.…”

Section: Resultsmentioning

confidence: 99%

Distinct mechanisms underlying cholesterol protection against alcohol-induced BK channel inhibition and resulting vasoconstriction

Bisen

Seleverstov

Belani

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Alcohol (ethanol) at concentrations reached in blood following moderate to heavy drinking (30–80 mM) reduces cerebral artery diameter via inhibition of voltage- and calcium-gated potassium channels of large conductance (BK) in cerebral artery smooth muscle. These channels consist of channel-forming α and regulatory β1 subunits. A high-cholesterol diet protects against ethanol-induced constriction via accumulation of cholesterol within the vasculature. The molecular mechanisms of this protection remain unknown. In the present work, we demonstrate that in vitro cholesterol enrichment of rat middle cerebral arteries significantly increased cholesterol within arterial tissues and blunted constriction by 50 mM of ethanol. Ethanol-induced BK channel inhibition in inside-out patches excised from freshly isolated cerebral artery myocytes was also abolished by cholesterol enrichment. Enrichment of arteries with enantiomeric cholesterol (ent-cholesterol) also blunted BK channel inhibition and cerebral artery constriction in response to ethanol. The similar protection of cholesterol and ent-cholesterol against ethanol action indicates that this protection does not require protein site(s) that specifically sense natural cholesterol. Cholesterol-driven protection against ethanol-induced BK channel inhibition and vasoconstriction was replicated in myocytes and middle cerebral arteries of C57BL/6 mice. BK β1 subunits are known to regulate vascular diameter and its modification by ethanol. However, blunting of an ethanol effect by in vitro cholesterol enrichment was observed in arteries and myocyte membrane patches from BK β1 (KCNMB1) knockout mice. Thus, BK β1 subunits are not needed for cholesterol protection against ethanol effect on BK channel function and cerebral artery diameter.

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Regulation of BK Channel Activity by Cholesterol and Its Derivatives

Bukiya

Dopico

2019

Advances in Experimental Medicine and Biology

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Cholesterol Tuning of BK Ethanol Response Is Enantioselective, and Is a Function of Accompanying Lipids

Cited by 32 publications

References 61 publications

Distinct Sensitivity of Slo1 Channel Proteins to Ethanol

Distinct Sensitivity of Slo1 Channel Proteins to Ethanol

Distinct mechanisms underlying cholesterol protection against alcohol-induced BK channel inhibition and resulting vasoconstriction

Regulation of BK Channel Activity by Cholesterol and Its Derivatives

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