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Ethanol inhibits KCNMA1. 135 / 135
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"Statin therapy exacerbates alcohol induced constriction of cerebral arteries via modulation of ethanol induced BK channel inhibition in vascular smooth muscle."
28865873
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"Therefore, BK channel inhibition by EtOH results in arterial constriction."
24588122
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"The decreased BK current density was associated with decreased channel immunolabeling in the periphery of tolerant terminals, as revealed by quantitative confocal analysis showing that chronic ethanol[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
15963352
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"Insertion of higher concentrations (40% molar ratio) of cholesterol into the DOPE/SPM bilayer, however, leads to strong ethanol inhibition of the BK channel."
22140451
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"Another intriguing possibility would be that excessive cholesterol directly interferes with EtOH sensing site (s) on BK channel protein precluding EtOH induced BK channel inhibition."
24588122
sparser
"Statin exacerbation of AICAC is underlied by statin-driven amplification of ethanol-induced BK channel inhibition."
28865873
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"Ethanol induced BK channel inhibition is increased with age."
29391966
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"Therefore, BK channel inhibition by ethanol results in cerebral artery constriction [XREF_BIBR, XREF_BIBR]."
29391966
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"Consistently, our results show that aged induced increase in BK beta1 protein levels are paralleled by an increase in basal BK channel activity and degree of ethanol induced BK channel inhibition in membrane patches from freshly isolated cerebral artery myocytes."
29391966
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"Indeed, age dependent increase in ethanol induced vasoconstriction was paralleled by an age dependent increase in ethanol induced BK channel inhibition in cerebral artery myocytes (XREF_FIG)."
29391966
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"Cholesterol antagonism of alcohol inhibition of smooth muscle BK channel requires cell integrity and involves a protein kinase C dependent mechanism (s)."
33383194
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"Although age dependent increase in BK beta1 subunit protein level and function paralleled the increase in ethanol induced constriction and ethanol induced BK channel inhibition, additional molecular players that could contribute to age dependent susceptibility of cerebral arteries to ethanol can not be ruled out."
29391966
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"This increase in ethanol induced BK channel inhibition was observed in excised membrane patches."
29391966
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"Thus, CLR blunting of alcohol-induced BK channel inhibition within vascular smooth muscle requires a cellular environment and cannot be replicated in cell-free membrane patches ( xref )."
33383194
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"As rats grew older, the degree of ethanol induced BK channel inhibition increased significantly from virtually no effect in myocyte membrane patches of 50 g rats to up to 25-30% inhibition in 250 g and 440 g groups (XREF_FIG)."
29391966
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"This increase in ethanol induced BK channel inhibition with age is consistent with the increased susceptibility of cerebral arteries from ageing animals to ethanol induced constriction (XREF_FIG and XREF_FIG)."
29391966
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"This increase is paralleled by the increase in the levels of BK channel beta1 protein in cerebral artery myocytes and in the degree of ethanol induced BK channel inhibition in membrane patches from cerebral artery myocytes themselves."
29391966
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"Cholesterol represents one of the critical membrane lipids that control the degree of ethanol induced BK channel inhibition and resulting vasoconstriction [XREF_BIBR, XREF_BIBR]."
29391966
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"When cholesterol content was increased to 40% of total lipid, single BK channel activity in DOPE/SPM/cholesterol bilayers was dramatically inhibited by ethanol."
22140451
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"Our study demonstrates for the first time statin 's ability to exacerbate the vascular effect of a widely consumed drug of abuse, this exacerbation being driven by statin modulation of ethanol induced BK channel inhibition in the VSM via CLR mediated mechanism."
28865873
sparser
"Our findings document that CLR antagonism of alcohol-induced BK channel inhibition requires cell integrity and is enabled by a PKC-dependent mechanism(s)."
33383194
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"Insertion of higher concentrations (40% molar ratio) of cholesterol into the DOPE and SPM bilayer, however, leads to strong ethanol inhibition of the BK channel."
22140451
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"Alcohol-induced BK channel inhibition, however, vanished in MCA myocytes from rats on the high-CLR diet ( xref – xref )."
33383194
sparser
"Here, CLR depletion in vitro reinstated BK channel inhibition by 50 mM alcohol in myocyte patches from rats on high-CLR chow ( xref – xref , xref )."
33383194
sparser
"CLR blunting of alcohol-induced BK channel inhibition in vascular smooth muscle requires a cellular environment."
33383194
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"Depending on multiple molecular determinants (e.g., intracellular calcium concentration, alternative splicing, subunit composition, posttranslational modifications, lipid microenvironment), ethanol can either potentiate or reduce BK channel-mediated currents (see [4] for review)."
38135755
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"Thus, ethanol induced BK channel inhibition, together with internal Ca 2+ release caused by ethanol itself, could synergistically favor the cell entering apoptosis."
19270242
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"Moreover, we have established for the first time that the CLR-driven reduction in alcohol-induced BK channel inhibition requires a cellular environment and involves a PKC-dependent mechanism(s)."
33383194
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"In wild-type myocytes, ethanol inhibited BK channel activity, whereas in the absence of the beta1 subunit, ethanol potentiated BK channel activity."
25249984
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"The ability of CLR enrichment in vitro to confer protection against alcohol-induced BK channel inhibition was further validated in the current work."
33383194
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"More importantly, the current work demonstrates that a high-CLR dietary intake in vivo also decreases alcohol-induced BK channel inhibition in artery myocytes ( xref , xref )."
33383194
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"Our earlier work using BK β1 subunit-lacking KCNMB 1 knock-out mice, however, ruled out the possible involvement of the BK β1 subunit in CLR antagonism of alcohol-induced BK channel inhibition and the resulting constriction of cerebral arteries ( xref )."
33383194
sparser
"In summary, we have established a critical role for cellular PKC-sensitive mechanism(s) in mediating the protective effect of CLR enrichment against alcohol-induced BK channel inhibition."
33383194
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"Kcnma1 in both regions was also dysregulated by ethanol dependence."
27432260
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"BK channel inhibition by pregnenolone and ethanol involves Ca 2+ -driven gating."
37846408
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"Inclusion of 23 mol% CLR into the lipid mixture results in ethanol-induced BK channel inhibition ( xref )."
27238266
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"Ethanol-induced cerebral artery constriction that results from ethanol-induced BK channel inhibition is also ablated in rat and mouse arteries following cholesterol depletion ( xref )."
27238266
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"Our findings document that CLR antagonism of alcohol induced BK channel inhibition requires cell integrity and is enabled by a PKC dependent mechanism (s)."
33383194
sparser
"BK β1 subunit facilitates ethanol-induced inhibition of β1-containing BK channel complexes."
27799321
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"Conversely, at ~ 10 muM but not ~ 2 muM intracellular [Ca (2+)], EtOH (0.3%) decreased the single BK channel activity."
24153429
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"It is noteworthy that vascular smooth muscle BK channel inhibition by ethanol translates into cerebral artery constriction, as shown with rat and mouse cerebral arteries pressurized in vitro."
22584144
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"Consistent with the evaluation of CLR-ethanol interaction on myogenic tone and the key role of BK channels in mediating ethanol induced cerebral artery constriction, electrophysiology on membrane patches excised from rat and mouse cerebral artery myocytes reveals that ethanol induced BK channel inhibition is lost after CLR depleting treatment."
22584144
sparser
"It is noteworthy that vascular smooth muscle BK channel inhibition by ethanol translates into cerebral artery constriction, as shown with rat and mouse cerebral arteries pressurized in vitro ( xref ; xref )."
22584144
sparser
"Consistent with the evaluation of CLR-ethanol interaction on myogenic tone and the key role of BK channels in mediating ethanol-induced cerebral artery constriction ( xref ), electrophysiology on membrane patches excised from rat and mouse cerebral artery myocytes reveals that ethanol-induced BK channel inhibition is lost after CLR-depleting treatment."
22584144
sparser
"Our study demonstrates for the first time statin’s ability to exacerbate the vascular effect of a widely consumed drug of abuse, this exacerbation being driven by statin modulation of ethanol-induced BK channel inhibition in the VSM via CLR-mediated mechanism."
28865873
sparser
"Several factors beyond the presence of BK beta 1 subunit contribute into the degree of ethanol-induced BK channel inhibition and resulting AICAC."
28865873
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"Inclusion of 23 mol% CLR into the lipid mixture results in ethanol induced BK channel inhibition."
27238266
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"Ethanol induced cerebral artery constriction that results from ethanol induced BK channel inhibition is also ablated in rat and mouse arteries following cholesterol depletion."
27238266
sparser
"Thus, statin administration exacerbates ethanol-induced BK channel inhibition when compared to high CLR diet."
28865873
sparser
"Our earlier work showed that AICAC and ethanol-induced BK channel inhibition was drastically ablated in KCNMB1 beta1-lacking knockout mouse arteries/myocytes [ xref ]."
28865873
sparser
"Thus, the exacerbation of AICAC and underlying ethanol-induced BK channel inhibition could potentially arise from an atorvastatin-driven increase in the amount and/or function of BK beta 1 subunits."
28865873
sparser
"To test whether suppression of ethanol-induced BK channel inhibition in high CLR diet+atorvastatin group was due to removal of excessive CLR from arterial wall, we incubated dissected MCAs in PSS that contained MbetaCD complex with CLR."
28865873
sparser
"Thus, while atorvastatin exacerbates ethanol-induced BK channel inhibition, statin treatment diminishes basal channel function."
28865873
sparser
"Atorvastatin exacerbation of ethanol-induced BK channel inhibition is removed upon artery in vitro enrichment with CLR."
28865873
sparser
"Our recent work using CLR manipulation in vitro , demonstrated that excessive CLR in cerebral artery vasculature blunted ethanol-induced BK channel inhibition [ xref ]."
28865873
sparser
"In contrast to BK channel activation, ethanol-induced BK channel inhibition in both rats and mice has been demonstrated to play a central role in ethanol-induced cerebral artery constriction (Liu et al., xref ; Bukiya et al., xref )."
25538625
sparser
"CLR enrichment prevented development of ethanol-induced BK channel inhibition, and rendered BK NPo undistinguishable from that observed upon ethanol perfusion in high CLR diet + placebo group ( xref )."
28865873
sparser
"Thus, atorvastatin exacerbation of ethanol-induced BK channel inhibition was achieved via statin removal of excessive CLR from the artery."
28865873
sparser
"Mechanistically, we established that statin exacerbation of AICAC was underlied by statin-induced potentiation of VSM BK channel inhibition by ethanol."
28865873
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"In contrast to BK channel activation, ethanol induced BK channel inhibition in both rats and mice has been demonstrated to play a central role in ethanol induced cerebral artery constriction."
25538625
sparser
"A rather surprising but straightforward conclusion from our work is that atorvastatin did not display any pleiotropic effects in exacerbating AICAC and ethanol-induced BK channel inhibition, as statin effect was robustly reversed by CLR enrichment in vitro ."
28865873
sparser
"However, the fact that increase in CLR level by 10–15% drove notable pharmacological consequences, argues in favor of a mechanism that is highly sensitive to CLR levels and/or being able to amplify CLR effect on alcohol-induced BK channel inhibition and resulting vasoconstriction."
28865873
sparser
"Therefore, BK channel inhibition by EtOH results in arterial constriction."
24588122
reach
"Although ethanol targets BK channels through direct interaction, how ethanol mediated BK channel activation causes behavioral intoxication is poorly understood."
31308408
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"Distinct mechanisms underlying cholesterol protection against alcohol induced BK channel inhibition and resulting vasoconstriction."
27565113
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"Ethanol induced BK channel inhibition in inside-out patches excised from freshly isolated cerebral artery myocytes was also abolished by cholesterol enrichment."
27565113
reach
"Cholesterol driven protection against ethanol induced BK channel inhibition and vasoconstriction was replicated in myocytes and middle cerebral arteries of C57BL/6 mice."
27565113
reach
"Despite more than a decade of research, the molecular mechanisms that mediate and control ethanol induced BK channel inhibition and the resulting cerebral artery constriction continue to be unraveled."
27565113
reach
"Thus, BK channel inhibition by ethanol results in arterial constriction."
27565113
reach
"Ethanol induced BK channel inhibition is independent of alcohol metabolism and freely diffusible cytosolic signals."
27565113
reach
"To determine whether cholesterol blunts alcohol induced BK channel inhibition, we used a conventional patch-clamp approach to record alcohol responses of BK channels in freshly isolated myocytes from control vs. cholesterol enriched middle cerebral arteries of rat."
27565113
sparser
"Another intriguing possibility would be that excessive cholesterol directly interferes with EtOH-sensing site(s) on BK channel protein precluding EtOH-induced BK channel inhibition."
24588122
reach
"PKC blockers diminish ethanol potentiation of BK channel activity in GH4/C1 cells but have no effect on GH4 and C1-STREX cells."
25538625
sparser
"Inclusion of 23 mol% cholesterol into the lipid mixture results in ethanol-induced BK channel inhibition (Bukiya et al., xref )."
25538625
reach
"Inclusion of 23 mol% cholesterol into the lipid mixture results in ethanol induced BK channel inhibition."
25538625
sparser
"BK channel inhibition by pregnenolone and ethanol involves Ca 2+ -driven gating."
37846408
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"As previously reported [XREF_BIBR, XREF_BIBR], 50 mM ethanol significantly reduced BK channel activity by = ~ 20% (XREF_FIG)."
27565113
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"Cholesterol protection against alcohol induced BK channel inhibition and resulting cerebral artery constriction is unlikely to be mediated by a protein site that is specific for natural cholesterol."
27565113
reach
"Thus, both cholesterol and ent-cholesterol were able to abolish ethanol induced BK channel inhibition (XREF_FIG vs. XREF_FIG)."
27565113
reach
"The similar ability of cholesterol and ent-cholesterol to antagonize ethanol induced BK channel inhibition and resulting cerebral artery constriction argues against the idea that cholesterol control over an alcohol effect requires cholesterol recognition by a protein site that specifically recognizes natural cholesterol."
27565113
reach
"Blunting of ethanol induced BK channel inhibition and resulting cerebral artery constriction by cholesterol enrichment does not require the presence of the BK beta1 subunit."
27565113
reach
"Therefore, we set out to determine whether cholesterol driven protection against ethanol induced BK channel inhibition requires the presence of beta1 protein."
27565113
reach
"To ensure that cholesterol blunting of ethanol induced BK channel inhibition is present when ethanol induced inhibition is comparable with inhibition observed in myocytes from wt mice, we performed experiments at higher levels of calcium that would enable ethanol induced BK channel inhibition in the absence of BK beta1 subunits [XREF_BIBR]."
27565113
reach
"As expected, at a higher calcium level (300 muM), ethanol induced BK channel inhibition was readily observed in membrane patches of cerebral artery myocytes from KCNMB1 KO mice (XREF_FIG)."
27565113
sparser
"Ethanol-induced BK channel inhibition is increased with age."
29391966
sparser
"Therefore, BK channel inhibition by ethanol results in cerebral artery constriction [ xref , xref ]."
29391966
sparser
"Consistently, our results show that aged-induced increase in BK β 1 protein levels are paralleled by an increase in basal BK channel activity and degree of ethanol-induced BK channel inhibition in membrane patches from freshly isolated cerebral artery myocytes."
29391966
sparser
"We used inside-out patches with Ca 2+ free in the bath solution set at 30 μ M. This concentration of Ca 2+ is reached in the vicinity of cerebral artery myocyte BK channel during myocyte constriction and is known to favor ethanol-induced inhibition of the cerebral artery BK channel [ xref , xref ]."
29391966
sparser
"As rats grew older, the degree of ethanol-induced BK channel inhibition increased significantly from virtually no effect in myocyte membrane patches of 50 g rats to up to 25–30% inhibition in 250 g and 440 g groups ( xref )."
29391966
sparser
"This increase in ethanol-induced BK channel inhibition with age is consistent with the increased susceptibility of cerebral arteries from ageing animals to ethanol-induced constriction ( xref and xref )."
29391966
sparser
"This increase is paralleled by the increase in the levels of BK channel β 1 protein in cerebral artery myocytes and in the degree of ethanol-induced BK channel inhibition in membrane patches from cerebral artery myocytes themselves."
29391966
sparser
"Indeed, age-dependent increase in ethanol-induced vasoconstriction was paralleled by an age-dependent increase in ethanol-induced BK channel inhibition in cerebral artery myocytes ( xref )."
29391966
sparser
"This increase in ethanol-induced BK channel inhibition was observed in excised membrane patches."
29391966
sparser
"Although age-dependent increase in BK β 1 subunit protein level and function paralleled the increase in ethanol-induced constriction and ethanol-induced BK channel inhibition, additional molecular players that could contribute to age-dependent susceptibility of cerebral arteries to ethanol cannot be ruled out."
29391966
reach
"We recently showed that a high-cholesterol diet protects against ethanol induced BK channel inhibition and resulting cerebral artery constriction via accumulation of cholesterol in the vasculature in vivo [XREF_BIBR]."
27565113
reach
"However, the effect of cholesterol on ethanol induced vasoconstriction is not monotonic : we have previously reported that cholesterol depletion from rat and mouse cerebral arteries blunts ethanol induced BK channel inhibition and the resulting cerebral artery constriction [XREF_BIBR]."
27565113
reach
"This probability is favored by the fact that both cholesterol and ent-cholesterol affect bilayer physical properties similarly, consistent with the similar ability to blunt alcohol induced BK channel inhibition and resulting vasoconstriction."
27565113
reach
"Thus, there seems to be an optimal level of cholesterol to fully enable ethanol inhibition of BK channel function and reduction of cerebral artery diameter."
27565113
reach
"One of the critical findings of our work is that cholesterol and ent-cholesterol possess a similar ability to blunt ethanol induced BK channel inhibition and the resulting constriction of cerebral arteries (XREF_FIG, XREF_FIG, XREF_FIG, XREF_FIG)."
27565113
reach
"In the case of beta1 subunit containing BK channels, the similar ability of cholesterol and ent-cholesterol to enhance BK channel function may hold the key to unraveling the precise mechanism by which both steroids blunt alcohol induced BK channel inhibition and the resulting cerebral artery constriction (XREF_FIG - XREF_FIG)."
27565113
reach
"Ethanol is able to perturb Ca 2+ -driven gating of slo1 and Methanobacterium thermoautotrophicum (MthK) channels."
27238266
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"If a cholesterol driven decrease in ethanol partition coefficient into the membrane underlies cholesterol antagonism of ethanol 's effect on BK channel function and cerebral artery diameter, then the described ethanol sensing site seems unlikely to play a major role in the ethanol induced BK channel inhibition that was observed in our experiments and that is routinely reported in the presence of beta1 subunits and high levels of Ca 2+ i [XREF_BIBR, XREF_BIBR]."
27565113
sparser
"Ethanol-induced BK channel inhibition in inside-out patches excised from freshly isolated cerebral artery myocytes was also abolished by cholesterol enrichment."
27565113
sparser
"Cholesterol-driven protection against ethanol-induced BK channel inhibition and vasoconstriction was replicated in myocytes and middle cerebral arteries of C57BL/6 mice."
27565113
sparser
"Despite more than a decade of research, the molecular mechanisms that mediate and control ethanol-induced BK channel inhibition and the resulting cerebral artery constriction continue to be unraveled."
27565113
sparser
"Thus, BK channel inhibition by ethanol results in arterial constriction."
27565113
sparser
"Ethanol-induced BK channel inhibition is independent of alcohol metabolism and freely diffusible cytosolic signals."
27565113
sparser
"To determine whether cholesterol blunts alcohol-induced BK channel inhibition, we used a conventional patch-clamp approach to record alcohol responses of BK channels in freshly isolated myocytes from control vs. cholesterol-enriched middle cerebral arteries of rat."
27565113
sparser
"Ethanol-induced BK channel inhibition could be clearly observed during the 3–7 min of ethanol application."
27565113
sparser
"Pre-incubation of cerebral arteries with MβCD/cholesterol complex totally blunted ethanol-induced BK channel inhibition ( xref right column, xref )."
27565113
sparser
"Considering that cholesterol antagonism of ethanol’s effect was found in cell-free myocyte membranes, cholesterol protection against ethanol-induced BK channel inhibition and resulting vasoconstriction are independent of freely diffusible cytosolic signals and cell metabolism of cholesterol or ethanol."
27565113
sparser
"Cholesterol protection against alcohol-induced BK channel inhibition and resulting cerebral artery constriction is unlikely to be mediated by a protein site that is specific for natural cholesterol."
27565113
sparser
"Thus, both cholesterol and ent -cholesterol were able to abolish ethanol-induced BK channel inhibition ( xref vs. xref )."
27565113
sparser
"The similar ability of cholesterol and ent -cholesterol to antagonize ethanol-induced BK channel inhibition and resulting cerebral artery constriction argues against the idea that cholesterol control over an alcohol effect requires cholesterol recognition by a protein site that specifically recognizes natural cholesterol."
27565113
sparser
"Blunting of ethanol-induced BK channel inhibition and resulting cerebral artery constriction by cholesterol enrichment does not require the presence of the BK β1 subunit."
27565113
sparser
"Therefore, we set out to determine whether cholesterol-driven protection against ethanol-induced BK channel inhibition requires the presence of β1 protein."
27565113
reach
"Ethanol induced BK channel inhibition could be clearly observed during the 3-7 min of ethanol application."
27565113
reach
"Pre-incubation of cerebral arteries with MbetaCD and cholesterol complex totally blunted ethanol induced BK channel inhibition (XREF_FIG right column, XREF_FIG)."
27565113
reach
"Considering that cholesterol antagonism of ethanol 's effect was found in cell-free myocyte membranes, cholesterol protection against ethanol induced BK channel inhibition and resulting vasoconstriction are independent of freely diffusible cytosolic signals and cell metabolism of cholesterol or ethanol."
27565113
reach
"Slo channels have ethanol binding sites and are generally inhibited by ethanol, but their responses vary depending on subunit composition, modification by phosphorylation, and the lipid microenvironment."
33870197
sparser
"To ensure that cholesterol blunting of ethanol-induced BK channel inhibition is present when ethanol-induced inhibition is comparable with inhibition observed in myocytes from wt mice, we performed experiments at higher levels of calcium that would enable ethanol-induced BK channel inhibition in the absence of BK β1 subunits [ xref ]."
27565113
sparser
"As expected, at a higher calcium level (300 μM), ethanol-induced BK channel inhibition was readily observed in membrane patches of cerebral artery myocytes from KCNMB1 KO mice ( xref )."
27565113
sparser
"We recently showed that a high-cholesterol diet protects against ethanol-induced BK channel inhibition and resulting cerebral artery constriction via accumulation of cholesterol in the vasculature in vivo [ xref ]."
27565113
sparser
"However, the effect of cholesterol on ethanol-induced vasoconstriction is not monotonic: we have previously reported that cholesterol depletion from rat and mouse cerebral arteries blunts ethanol-induced BK channel inhibition and the resulting cerebral artery constriction [ xref ]."
27565113
sparser
"One of the critical findings of our work is that cholesterol and ent -cholesterol possess a similar ability to blunt ethanol-induced BK channel inhibition and the resulting constriction of cerebral arteries ( xref , xref , xref , xref )."
27565113
reach
"The inhibitory impact of ACA on EtOH induced BK channel activation did not change single channel conductance which indicates that ACA does not interfere with potassium ions passing through the channel, neither does EtOH affect this ion passage."
23785316
sparser
"In the case of β1 subunit-containing BK channels, the similar ability of cholesterol and ent -cholesterol to enhance BK channel function may hold the key to unraveling the precise mechanism by which both steroids blunt alcohol-induced BK channel inhibition and the resulting cerebral artery constriction ( xref – xref )."
27565113
sparser
"This probability is favored by the fact that both cholesterol and ent -cholesterol affect bilayer physical properties similarly, consistent with the similar ability to blunt alcohol-induced BK channel inhibition and resulting vasoconstriction."
27565113
sparser
"Notably, the BK channel beta1 subunit enables BK channel inhibition by alcohol [ xref ], and also defines sensitivity of vascular smooth muscle BK channel to CLR [ xref ]."
33537157
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"Collectively, present determinations from HA modeling and previous findings strongly argue that ethanol perturbs BK channel function in the absence of noticeable changes in voltage sensor function."
27799321
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"Ethanol reversibly increased neurohypophysial BK channel activity (EC50, 22 mM; maximal effect, 100 mM)."
10432342
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"The inhibitory impact of ACA on the EtOH mediated increase of BK channel activity implicates that ACA has to be carefully taken into account if EtOH effects are studied."
23785316
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"Other studies have reported that alcohol inhibits BK channel activity, suggesting a role in acute alcohol sensitivity rather than in developing tolerance (68,73,77)."
40236633
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"Thus, beta1 modification of ethanol action results in ethanol reduction of BK channel activity when evaluated at low muM Ca 2+ i, an ethanol action reported with the native cerebrovascular channel."
27238266
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"By contrast, other studies have demonstrated that EtOH reduces BK channel activity, leading to depolarization and increased excitability, which could impair the development of tolerance (56,62,71)."
40236633