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Ethanol activates KCNMA1. 141 / 142
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"An initial ethanol induced BK channel activation (observed within 5 minutes) is favored by thin lipid bilayers, yet this activation vanishes and BK channel inhibition appears as bilayers consist of lipid species that form thicker bilayers."
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"Data demonstrate that ethanol potentiation of hslo channels is blunted by conical phospholipids but favored by cylindrical phospholipids, independently of phospholipid charge."
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"A detailed review of BK channel modulation by ethanol can be found in Chapter " Modulation of BK Channels by Ethanol " by Dopico."
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"Dopico et al. (1996) propose that changes in vasopressin release and diuresis, both effects of ethanol ingestion, are the result of BK channel activation by ethanol in neurohypophysial nerve terminal[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Electrophysiological data recorded in vivo are consistent with a model in which ethanol potentiation of SLO-1 produces intoxication in C. elegans by reducing excitatory neurotransmitter release."
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"Collectively, data discussed so far indicate that ethanol modulation of slo1 channel gating is coupled to Ca 2+ binding to this ion 's high-affinity sites in the slo1 protein CTD but not to ion binding to the slo1 channel 's low-affinity site for divalents."
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"The structural bases of beta1 modulation of ethanol action on slo1 channels remain speculative mainly because neither the structural basis of slo1 modulation by ethanol nor the structural bases of slo1 and beta1 subunit interaction are fully resolved."
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"Thus, chronic ethanol modulates BK channel sensitivity, density, and distribution pattern in NH terminals within the HNS explant, indicating that factors outside the HNS are not required for tolerance[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"BK channel activation by hypotonicity and ethanol is demonstrated in patch clamp experiments both in intact cells (cell attached configuration) and a subset of excised membrane patches (outside-out configuration)."
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"Ethanol increases BK channel activity in most types of cells including neurons ( Crowley et al., 2003; Jakab et al., 1997; Liu et al., 2003 ), leading to decreases in cell excitability, whereas BK cha[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Previous studies have shown that the calcium sensitive domains, RCK1 and the Ca 2+ bowl, are required for ethanol activation of the mammalian BK channel in vitro."
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"In the nematode Caenorhabditis elegans, ethanol activates the BK channel in vivo, and deletion of the worm BK channel, SLO-1, confers strong resistance to intoxication."
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"Alcohol begins to increase activity of the BK channel within seconds of exposure."
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"Our recent data indicate that kinases and phosphatases are involved in alcohol potentiation of the BK channel and the development of tolerance."
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"For example, although BK channels seem not to be constitutively phosphorylated by protein kinase A (PKA), phosphorylation by this kinase is necessary for alcohol potentiation of the BK channel."
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"Hypotonicity and ethanol modulate BK channel activity and chloride currents in GH4/C1 pituitary tumour cells."
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"For example, in rat neuroendocrine cells ethanol directly potentiates BK channel activity and is thought to contribute to ethanol suppression of neuropeptide secretion."
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"Altering the thickness of the lipid bilayer affects the time course of the acute response to alcohol and can completely prevent alcohol potentiation of the BK channel."
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"Clinically relevant concentrations of alcohol activate the BK channel in different species, suggesting a conserved mechanism of activation."
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"Moreover, ethanol treatment increases the activity of the slo-1 -dependent current in C. elegans sensory neurons, indicating that not only is slo-1 required for ethanol response, but it is also itself[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"In this system, ethanol potentiates BK channel activity which leads to an increase in firing and a suppression of hormone release."
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"Increased cholesterol in the plasma membrane can diminish the alcohol potentiation of the BK channel, potentially contributing to channel tolerance."
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"Ethanol modulates the mammalian BK channel in vitro independent of voltage and magnesium gating."
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"Indeed, PKC blockers diminished ethanol potentiation of BK channel activity in GH4/C1 cells."
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"In the rat neurohypophysial system, ethanol potentiates BK channel activity, triggers the internalization of ethanol sensitive channels, and alters gene expression so that replacement channels are refractory to ethanol."
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"Nevertheless, it is possible that the altered amount of cholesterol in a microdomain surrounding the BK channel caused by either acute or chronic alcohol exposure can temper alcohol 's effect on BK channels and thus contribute to the development of acute or chronic tolerance."
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"Of note, the distinct Ca requirement and high-affinity site involvement in cholesterol action on slo1 channels are not exclusive for this sterol, as it applies to ethanol activation of slo1 as well [80]."
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"In addition, we transgenically expressed the human BK channel in a slo-1 (null) mutant background, and found that the equivalent residue of the mammalian BK channel (T352) is critical for ethanol activation of the BK channel and intoxication in C. elegans."
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"The mammalian BK channel is also activated by ethanol, and this effect, as well as the channel’s basal activity, depends on the thickness of the lipid bilayer; channels that reside in thicker membrane are less basally active and are less activated by ethanol xref , xref , suggesting that movement of the BK channel into and out of areas of thicker membrane microenvironments may allow for very fast modulation of the effects of ethanol on this channel xref ."
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"Both of these uncharged compounds, cholic acid methyl ester and " cholic alcohol " (XREF_FIG), rapidly and reversibly increased BK channel activity (XREF_FIG B and XREF_TABLE) in the same way as cholic acid did (see XREF_FIG and XREF_TABLE)."
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"Insertion of increasing amounts of nat-CHS into a POPE and POPS bilayer is associated with linearly increasing suppression of ethanol activation of the BK channel XREF_BIBR."
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"Electrophysiology was performed on intact C. elegans neurons, which showed that ethanol increased BK channel currents but failed to do so in slo-1 null mutant neurons."
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"These data suggest that ethanol is causing regulation of specific KCNMA1 mRNAs."
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"Furthermore, kinetic analysis showed that cholesterol 's effect on single channel activity parameters (such as open and closed times) mirror that of ethanol, indicating that cholesterol and ethanol may target common hslo channel dwelling states."
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"XREF_BIBR found that alcohol causes remodeling of the BK channel transcript landscape by regulating the stability of a subset of these transcripts, such that the relative number of transcripts encoding highly sensitive channels are decreased, whereas that of transcripts encoding less sensitive channel proteins are increased, consistent with tolerance."
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"Previously, we showed that 50 mm alcohol increases both alpha and alphabeta4 BK channel open probability, but only alpha BK develops acute tolerance to this effect."
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"An asparagine substitution of residue K361 of the mouse BK α subunit was shown to abolish ethanol’s ability to increase BK channel steady-state activity without affecting unitary conductance, calcium sensitivity, or voltage sensitivity, thereby providing a unique opportunity to selectively disrupt the direct effect of ethanol on BK channels [15]."
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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."
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"Thus, Ca 2+ binding to the Ca 2+ bowl appears to be dispensable for both ethanol modulation of human BK channel gating in vitro and for intoxication behavior linked to ethanol modification of SLO-1 channel gating in vivo shown here."
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"The SLO-1 protein is activated by ethanol in vivo, an effect that would inhibit neuronal activity."
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"Increased cholesterol in the bilayer (which will increase membrane thickness and rigidity and promote formation of lipid rafts) can diminish the alcohol potentiation of the BK channel [XREF_BIBR], potentially contributing to channel tolerance."
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"Previous studies have shown that the calcium-sensitive domains, RCK1 and the Ca 2+ bowl, are required for ethanol activation of the mammalian BK channel in vitro ."
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"This latter finding is consistent with previous electrophysiological recordings, which showed that ethanol failed to modulate the mammalian BK channel when both the RCK1 and Ca 2+ bowl domains were neutralized."
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"For example, ethanol-induced BK channel activation in GH3 and GH4/C1 rat pituitary tumor cells would likely lead to inhibition of hormone release ( xref ; xref )."
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"It should be noted however, that acetaldehyde, a major metabolite of ethanol, antagonizes ethanol-induced BK channel activation in excised patches from GH3 cells ( xref )."
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"The structural basis of ethanol activation of slo1 channels and its relation to Ca 2+ i is provided under the next subheading."
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"For instance, the potentiation of mslo activity induced by ethanol decreases when intracellular Ca 2+ increases, meaning that BK channel activation by this alcohol is more marked when intracellular Ca 2+ is near basal conditions."
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"For example, expression of brain derived neurotrophic factor (Bdnf) and synaptophysin (Syp) were decreased while Kcnma1, Arl6ip5 and Camkk2 were increased by acute ethanol in PFC of Fyn null animals (XREF_SUPPLEMENTARY, lower panel) but were not regulated by ethanol in controls (XREF_SUPPLEMENTARY, upper panel)."
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"It has also been observed that ethanol can increase BK channel activity in a tissue dependent manner, which was initially related to BK isoforms and/or differential beta subunit expression in various tissues."
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"In the nematode Caenorhabditis elegans , ethanol activates the BK channel in vivo , and deletion of the worm BK channel, SLO-1, confers strong resistance to intoxication."
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"In addition, we transgenically expressed the human BK channel in a slo-1(null) mutant background, and found that the equivalent residue of the mammalian BK channel (T352) is critical for ethanol activation of the BK channel and intoxication in C. elegans ."
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"Additionally, exploring other RCK1 domain residue differences between the worm and mammalian channel may lead to novel insights into channel kinetics and ethanol activation of the BK channel."
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"Alcohol modulation of BK channel gating depends on beta subunit composition."
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"The authors also demonstrated that ethanol activates the BK channel in vivo, which leads to the inhibition of neuronal activity, and the hyperactivation of the BK channel leads to behavior similar to ethanol intoxication [42]."
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"Additionally, exploring other RCK1 domain residue differences between the worm and mammalian channel may lead to novel insights into channel kinetics and ethanol activation of the BK channel."
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"Filling this knowledge gap acquires particular relevance because ethanol action on BK channels appears to be beta subunit dependent; at physiological Ca 2+ i levels, neuronal and recombinant (slo1 and slo1+ beta4) channels are usually activated by ethanol, whereas vascular smooth muscle and recombinant slo1+ beta1 are usually inhibited."
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"Of note, the distinct Ca 2+ requirement and high-affinity site involvement in cholesterol action on slo1 channels are not exclusive for this sterol, as it applies to ethanol activation of slo1 as well [ xref ]."
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"BK channel influences neuronal excitability and transmitter release and is potentiated by alcohol (Pietrzykowski et al., 2008)."
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"To investigate whether ACA specifically modulated EtOH-induced BK channel activation or, rather, ACA modulatory action extended to other BK channel activators, we tested the effect of internal ACA on Hypo-induced BK channel activation in outside-out recordings."
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"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 (Brodie et al., xref ; Treistman and Martin, xref )."
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"The studies also suggest that natural variation in dystrophin related genes may also contribute to alcohol-use disorders as BK channel activity is directly modulated by ethanol, and modifying any of these genes alters behavioral sensitivity to alcohol."
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"A Novel Peptide Restricts Ethanol Modulation of the BK Channel In Vitro and In Vivo."
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"The ethanol-induced inhibition of low-frequency firing neurons is attributable to ethanol activation of the BK channel ( xref )."
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"Other possibilities can not be excluded : CLR antagonism of slo1 channel potentiation by ethanol may be attributed to CLR making it more difficult for ethanol molecules to partition into the bilayer and thus reaching eventual channel subunit targets."
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"In the hypothalamic-neurohypophysial model system there is strong evidence that BK channel activity is modulated by ethanol exposure in ways that could underlie chronic tolerance."
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"Clinically relevant concentrations of EtOH increased somatic but not dendritic BK channel open probability."
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"Moreover, as far as Ca 2+ i is able to interact with one of its physiological recognition sites, the BK channel is activated by ethanol (Liu et al., xref )."
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"The structural basis of ethanol activation of slo1 channels and its relation to Ca 2+ i is provided in a separate section."
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"Together, our behavioral and electrophysiological results demonstrate that the T352I mutation selectively disrupts ethanol modulation of the BK channel."
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"In neurohypophyseal axon terminals, ethanol potentiation of BK channel activity leads to a reduction in neuropeptide release."
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"Likewise, ethanol-induced BK channel activation in GH3 and GH4/C1 rat pituitary tumor cells would likely lead to inhibition of hormone release by alcohol (Jakab et al., xref , xref )."
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"In addition to internalization of membrane BK channels as a mechanism underlying rapid tolerance to ethanol, alcohol driven changes in the brain BK channel splice variant profile have been reported, this arrangement being controlled by microRNAs."
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"The ethanol " opposing " effects on macroscopic current (XREF_FIG) were matched by the results describing drug behavior at single-channel resolution, with the alcohol increasing BK channel steady-state activity (NPo) at 0.3 muM Ca 2+ i while inhibiting activity at 30 muM Ca 2+ i (XREF_SUPPLEMENTARY)."
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"Ethanol-induced BK channel activation has been proposed as a mechanism for the neuroprotective effect of ethanol preconditioning against post-ischemic neuronal injury in mice (Wang et al., xref )."
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"Ethanol Increases BK Channel Open Probability."
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"Moreover, as far as Ca 2+ i is able to interact with one of its physiological recognition sites, the BK channel is activated by ethanol."
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"The structural basis of ethanol activation of slo1 channels and its relation to Ca 2+ i is provided in a separate section."
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"In worms, ethanol activates SLO-1 in vivo, causing a large efflux of potassium ions, hyperpolarizing the cell and depressing neuronal excitability, which is a major cause of intoxication in C. elegans XREF_BIBR."
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"The mammalian BK channel is also activated by ethanol, and this effect, as well as the channel 's basal activity, depends on the thickness of the lipid bilayer; channels that reside in thicker membrane are less basally active and are less activated by ethanol XREF_BIBR, XREF_BIBR, suggesting that movement of the BK channel into and out of areas of thicker membrane microenvironments may allow for very fast modulation of the effects of ethanol on this channel XREF_BIBR."
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"Likewise, ethanol induced BK channel activation in GH3 and GH4/C1 rat pituitary tumor cells would likely lead to inhibition of hormone release by alcohol."
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"As mentioned above, ethanol activation of slo1 channels has been linked to modulation of Ca 2+ -driven gating."
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"Moreover, when studied in the same expression system, Ca 2+ i -sensitive slo1 is activated by ethanol while Na + -gated slo2 and H + -gated slo3, no matter the concentration of activating ion, remain ethanol-resistant."
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"Ethanol induced BK channel activation has been proposed as a mechanism for the neuroprotective effect of ethanol preconditioning against post-ischemic neuronal injury in mice."
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"Consistently with a key role for β1 in blunting slo1 channel activation by ethanol and favoring drug-induced inhibition, ethanol fails to activate native cerebral artery BK channels in KCNMB1 knockout mice (Bukiya et al., xref )."
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"In this case, ethanol increased the BK channel NP o (XREF_FIG : t (6) = 4.78, p < 0.05), which was blocked by the BK inhibitor as expected (XREF_FIG : t (6) = 3.36, p < 0.05)."
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"Ethanol modulation of BK channel activity has been consistently reported in membrane patches that expressed either native or recombinant channel proteins and after reconstitution of channel subunits into artificial planar lipid bilayers of simple composition."
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"Cholesterol antagonism of slo1 channel activation by ethanol, however, has been attributed to a variety of factors."
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"As mentioned above, ethanol activation of slo1 channels has been linked to modulation of Ca 2+ -driven gating."
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"Moreover, when studied in the same expression system, Ca 2+ i -sensitive slo1 is activated by ethanol while Na + -gated slo2 and H + -gated slo3, no matter the concentration of activating ion, remain ethanol resistant."
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"Because the earliest observed benzyl alcohol–induced histone H4 acetylation spike was centered over element 55b, we hypothesized that this acetylation increase might represent the first step in the benzyl alcohol-induced activation of the slo gene ( xref )."
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"Ethanol-induced slo1 channel activation is also controlled by phosphorylation/dephosphorylation processes."
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"d) Phosphorylation of BK Channels and/or Channel associated Proteins Ethanol induced slo1 channel activation is also controlled by phosphorylation and dephosphorylation processes."
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"In worm, slo mutations decrease ethanol sensitivity, while in flies, slo is transcriptionally induced by ethanol exposure, causing tolerance XREF_BIBR, XREF_BIBR."
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"Cholesterol antagonism of slo1 channel activation by ethanol, however, has been attributed to a variety of factors."
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"In BK, the linker that connects the S6 gate to the RCK domains forms a passive spring with the gating ring and is involved in Ca 2+ i -dependent activation, the latter being required for ethanol potentiation of slo1 channels."
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"Previous work showed that ethanol potentiates BK channel open probability in isolated hypothalamo-hypophyseal neurons and nucleus accumbens slices."
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"For example, ethanol induced BK channel activation in GH3 and GH4/C1 rat pituitary tumor cells would likely lead to inhibition of hormone release."
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"Importantly, MaxiK channel activation by alcohol decays in ~ 10 min which correlates with decreased ALCOREX expression in hypothalamo-neurohypophysial system explants exposed to alcohol [XREF_BIBR]."
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"Intoxicating levels of ethanol (10-100 mM) usually increase the open probability (Po) of homomeric slo1 channels while decreasing Po of beta1 containing BK complexes (Dopico et al. 2014."
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"In contrast, ethanol induced BK channel activation of either or both neuronal and cerebral microvascular endothelial cells has been proposed as a key mechanism for the neuroprotective effect of ethanol preconditioning against post-ischemic neuronal injury in mice."
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"Thus, while ethanol increases the apparent calcium affinity of both slo1 and slo1+ beta1 channels, ethanol induced disruption of allosteric coupling in slo1+ beta1 override drug induced decrease in K d, leading to overall decrease in Po."
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"Previous studies have shown that slo is slightly induced by both benzyl alcohol and ethanol sedation XREF_BIBR, XREF_BIBR."
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"We previously determined that clinically relevant doses of ethanol modulate the activity of the BK channel in cell membranes ( Dopico et al., 1998 ), or when they are inserted into artificial bilayers[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"It should be noted however, that acetaldehyde, a major metabolite of ethanol, antagonizes ethanol induced BK channel activation in excised patches from GH3 cells."
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"BK channel Po was significantly increased by extracellular application of EtOH and ACA in combination."
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"The structural basis of ethanol activation of slo1 channels and its relation to Ca 2+ i is provided under the next subheading."
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"Thus, when actin filaments are destabilized, then EtOH induces a potentiation of BK channel activity, with either high or low internal Mg 2+."
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"For instance, the potentiation of mslo activity induced by ethanol decreases when intracellular Ca 2+ increases, meaning that BK channel activation by this alcohol is more marked when intracellular Ca 2+ is near basal conditions (Dopico et al., xref , xref )."
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"For example, 1 mM and 10 mM alcohol increased BK channel open probability by 1.45 and 2.5 fold, respectively, in excised patches from the soma of NAc neurons [XREF_BIBR]."
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"On the other hand, ethanol directly modulates BK channel activity in a variety of systems, including rat neurohypophysial nerve endings, primary sensory dorsal root ganglia, nucleus accumbens neurons, Caenorhabditis elegans type-IV dopaminergic CEP neurons, and nonneuronal preparations, such as rat pituitary cells, cerebrovascular myocytes and human umbilical vein endothelial cells."
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"The site recognizes ethanol molecules and mediates ethanol induced BK channel activation that is observed in homomeric (only alpha subunits) channels at calcium levels below 30 muM [XREF_BIBR, XREF_BIBR]."
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"Ethanol modulation of BK channel activity is influenced by the channel subunit composition."
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"Thus, as far as activating Ca 2+ can be sensed by at least one of the channel high-affinity Ca 2+ sensors, ethanol is able to increase BK channel activity."
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"In most neuronal and neuroendocrine preparations at physiological intracellular calcium levels, EtOH increases BK channel activity."
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"Results : Extracellular EtOH raised BK channel activity."
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"Typically, the BK channel is potentiated by alcohol, although in some tissues, it is inhibited."
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"Indeed, 50 mM ethanol increased BK channel activity from MSNs, and this increase was sustained throughout the recording session."
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"In spite of recent advances in our understanding of how ethanol at concentrations found in blood during moderate-heavy alcohol intoxication (50-100 mM) modulates BK channel activity and thus cell physiology, the gating mechanisms underlying such modulation remain unknown."
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"BK channels as integral membrane proteins are prominent cellular targets for EtOH, which is well documented to increase BK channel activity via a Ca 2+ and protein kinase C (PKC) dependent mechanism in a dose dependent manner."
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"In contrast, in neurons from beta 4 KO mice, 50 mM ethanol initially potentiated BK channel activity, but the activity rapidly returned to predrug levels, indicating the development of acute tolerance."
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"EtOH as well as hypotonicity (Hypo) induce cell swelling and both increase BK channel activity."
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"Application of 30 mM isoosmolar EtOH increased BK channel Po significantly at low, but not at high [Ca 2+] i."
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"EtOH potentiates Slo-1, causing intoxication by reducing neurotransmitter release (33,34)."
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"As known from previous experiments (see also Table XREF_TABLE) BK channel Po was increased by EtOH when applied subsequent to a control solution."
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"The authors also demonstrated that ethanol activates the BK channel in vivo, which leads to the inhibition of neuronal activity, and the hyperactivation of the BK channel leads to behavior similar to ethanol intoxication [ xref ]."
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"BK channel Po was significantly increased by the first EtOH application."
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"Ethanol modulation of BK channel activity has been consistently reported in vitro using highly simplified model systems."
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"To investigate whether ACA specifically modulated EtOH induced BK channel activation or, rather, ACA modulatory action extended to other BK channel activators, we tested the effect of internal ACA on Hypo induced BK channel activation in outside-out recordings."
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"SLO-1 channel activity is increased by ethanol in vivo, an effect that would inhibit neuronal activity."
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"EtOH increases BK channel Po."
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"Magnesium (Mg² ) protects against the EtOH potentiation of BK channel activity."
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"Electrophysiological recordings have shown that in the absence of Mg² , EtOH notably increases the likelihood of BK channel openings."
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"Our experiments show that intracellular ACA prevents the EtOH mediated increment of BK channel activity."
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"It could be argued that the inhibitory impact of internal ACA on EtOH related augmentation of BK channel activity reflects a kind of ' protective ' effect under acute EtOH exposure, maintaining neuronal activity and excitability."
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"Ethanol activation of the SLO-1 current was also observed in motor neurons that directly control locomotion."
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"Since the functional efficiency of some PKC species relies on intracellular Ca 2+ availability ACA could achieve its counteracting effect on EtOH induced BK channel activation by engaging with the Ca 2+ influx into the cytosol."
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"The behavioral significance of BK channel potentiation by ethanol is however unclear."
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"In contrast, ethanol (up to 100 mM) failed to increase cell body BK channel activity."
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"The findings of our study demonstrate that internal ACA at high nanomolar concentrations is able to counteract BK channel potentiation by EtOH at low Ca 2+ levels."
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"Some studies have reported that EtOH directly enhances BK channel opening, increasing K efflux and leading to neuronal hyperpolarization (69,114)."
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"Studies across various cell lines and animal models, including C. elegans, fruit flies and rodents, have indicated that alcohol modulates BK channel activity, influencing both acute and chronic behavioral responses to alcohol (117)."
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