Trends in Neurosciences
ReviewBK Channels: mediators and models for alcohol tolerance
Section snippets
Behavioral tolerance
Behavioral tolerance is a common occurrence following exposure to drugs of abuse, characterized by reduced drug effect on a behavioral parameter, either via altered metabolism of the drug or via altered functionality, where the effects of the drug decrease in spite of unaltered concentration. Consequently, the user will escalate drug intake, to maintain the desired effect, with devastating results. There are multiple classes of tolerance, defined by the timeframe and pattern (e.g. constant
BK channel
The large conductance Ca2+- and voltage-activated K+ (BK) channel represents a functional subtype of a large group of K+ channels 31, 32, 33, 34 that play a dominant role in shaping neuronal activity 18, 24, 35, 36. It is formed by the association of α core and β auxiliary subunits. The α core subunit possesses many of the common structural features of voltage-gated K+ channels, including an ion-selective pore formed by transmembrane segments S5 and S6 and a voltage-sensing module formed by
The BK channel as a model for molecular tolerance
Adaptation of BK to alcohol (molecular tolerance) involves both reduced sensitivity to the drug after exposure, which occurs within minutes, and a slower-developing declustering within groups of channels and subsequent internalization of channels from the plasma membrane (leading to decreased current density), measured in hours [39]. After 24-h exposure, BK channels remaining in the membrane are (i) less potentiated by acute challenge; (ii) less clustered; and (iii) less dense within remaining
Lipid environment affects the immediate and long-term response of BK to alcohol
Theories of molecular mechanisms of action of alcohol in the central nervous system have evolved from an earlier ‘lipid hypothesis’, in which actions of ethanol on neuronal membranes was explained mainly in terms of actions on membrane lipids, secondarily affecting proteins, to the recent ‘protein hypothesis’, which is predicated on findings (driven by molecular mutagenesis studies) that alcohol can interact directly with membrane proteins to affect function 39, 43, 44. Indeed, this change in
Epigenetics and tolerance: MicroRNA mediates a selective degradation of BK isoforms leading to tolerance
One of the more surprising results from the human genome project was the absence of a significantly greater number of genes in the human genome in comparison with ‘less complex’ species [63]. An explanation for this is emerging from our growing appreciation of epigenetic modulation, in which the gene DNA sequence is unchanged, but the expression of gene products is altered. A particularly important element of epigenetic modulation is the potential for influencing gene expression by environment
Phosphorylation significantly affects actions of alcohol
As with other ion channels, the activity of BK splice variants is controlled in part by kinases and phosphatases 15, 70, 71, 72, 73. Recent studies have made clear how post-translational modifications such as phosphorylation/dephosphorylation can control the response to alcohol 74, 75, 76, 77, as well as provide a potentially elegant mechanism for tolerance. Thus, a recent study demonstrated that the calcium/calmodulin-dependent protein kinase, CaMKII, is crucial in the effects of alcohol on
BK subunit composition predicts alcohol acute tolerance and consumption
Whereas the previous section describes a mechanism of tolerance related to isoform variability in the α subunit of the BK channel, in this section we will describe the influence of the BK auxiliary β subunits on tolerance. The BK channel, which is mainly understood to act as a ‘brake’ on neural activity 21, 78, 79 (although excitatory effects have also been reported [20]), is composed of a primary α protein, containing a pore that acts as a conduit for potassium ions, often combined with a
Concluding remarks
Here, we have presented data from several approaches that probe the response of the BK channel to ethanol, indicating that the response is more specific and interpretable than textbook doctrine would have suggested for alcohol–protein interactions just 20 years ago. The data described raise many interesting questions. Why are there so many different mechanisms to produce and modify BK alcohol tolerance? Clearly, the neuron finds it important to minimize the consequences of the influence of
References (86)
Effect of ethanol on cardiac single sodium channel gating
Forensic Sci. Int.
(2007)Modulation of action potential firing by iberiotoxin and NS1619 in rat dorsal root ganglion neurons
Neuroscience
(2003)Posttranscriptional regulation of BK channel splice variant stability by miR-9 underlies neuroadaptation to alcohol
Neuron
(2008)A central role of the BK potassium channel in behavioral responses to ethanol in C. elegans
Cell
(2003)Large-conductance, calcium-activated potassium channels: structural and functional implications
Pharmacol. Ther.
(2006)A seizure-induced gain-of-function in BK channels is associated with elevated firing activity in neocortical pyramidal neurons
Neurobiol. Dis.
(2008)Long-lasting increases in intrinsic excitability triggered by inhibition
Neuron
(2003)Cloning and functional characterization of novel large conductance calcium-activated potassium channel beta subunits, hKCNMB3 and hKCNMB4
J. Biol. Chem.
(2000)hKCNMB3 and hKCNMB4, cloning and characterization of two members of the large-conductance calcium-activated potassium channel beta subunit family
FEBS Lett.
(2000)Effect of ethanol on urine output in rats
Alcohol
(1985)
Rapid transient absorption and biliary secretion of enantiomeric cholesterol in hamsters
J. Lipid Res.
Acute alcohol tolerance is intrinsic to the BKCa protein, but is modulated by the lipid environment
J. Biol. Chem.
Partitioning of membrane molecules between raft and non-raft domains: insights from model-membrane studies
Biochim. Biophys. Acta
Role of cholesterol in the formation and nature of lipid rafts in planar and spherical model membranes
Biophys. J.
Disruption of lipid rafts inhibits P2X1 receptor-mediated currents and arterial vasoconstriction
J. Biol. Chem.
BK channels are linked to inositol 1,4,5-triphosphate receptors via lipid rafts: a novel mechanism for coupling [Ca(2+)](i) to ion channel activation
J. Biol. Chem.
Linker-gating ring complex as passive spring and Ca(2+)-dependent machine for a voltage- and Ca(2+)-activated potassium channel
Neuron
Regulation of the gating of BKCa channel by lipid bilayer thickness
J. Biol. Chem.
Epigenetic mechanisms in drug addiction
Trends Mol. Med.
Chronic ethanol exposure induces an N-type calcium channel splice variant with altered channel kinetics
FEBS Lett.
Expression of N-methyl-d-aspartate (NMDA) receptor subunits and splice variants in an animal model of long-term voluntary alcohol self-administration
Drug Alcohol Depend.
Reversible tyrosine protein phosphorylation regulates large conductance voltage- and calcium-activated potassium channels via cortactin
J. Biol. Chem.
Regulation of STREX exon large conductance, calcium-activated potassium channels by the beta4 accessory subunit
Neuroscience
Ion channels and intracellular signaling proteins as potential targets for novel therapeutics for addictive and depressive disorders
Pharmacol. Ther.
MAP kinase signaling in diverse effects of ethanol
Life Sci.
The mesolimbic dopamine-activating properties of ethanol are antagonized by mecamylamine
Eur. J. Pharmacol.
Alcohol and cardiovascular health: the razor-sharp double-edged sword
J. Am. Coll. Cardiol.
Ethanol targets: a BK channel cocktail in C. elegans
Trends Neurosci.
Pre- and post-synaptic mechanisms of synaptic strength homeostasis revealed by slowpoke and shaker K(+) channel mutations in Drosophila
Neuroscience
Research on tolerance: what can we learn from history?
Alcohol Clin. Exp. Res.
Low level of response to alcohol as a predictor of future alcoholism
Am. J. Psychiatry
Identification of a BK channel auxiliary protein controlling molecular and behavioral tolerance to alcohol
Proc. Natl. Acad. Sci. U. S. A.
Ethanol interactions with calcium-dependent potassium channels
Alcohol Clin. Exp. Res.
Sizing up ethanol-induced plasticity: the role of small and large conductance calcium-activated potassium channels
Alcohol Clin. Exp. Res.
Hyperpolarization-activated cation current (Ih) is an ethanol target in midbrain dopamine neurons of mice
J. Neurophysiol.
Ethanol sensitivity of BK(Ca) channels from arterial smooth muscle does not require the presence of the beta 1-subunit
Am. J. Physiol. Cell Physiol.
Somatic localization of a specific large-conductance calcium-activated potassium channel subtype controls compartmentalized ethanol sensitivity in the nucleus accumbens
J. Neurosci.
Alcohol tolerance in large-conductance, calcium-activated potassium channels of CNS terminals is intrinsic and includes two components: decreased ethanol potentiation and decreased channel density
J. Neurosci.
Distinct structural features of phospholipids differentially determine ethanol sensitivity and basal function of BK channels
Mol. Pharmacol.
Essential role for smooth muscle BK channels in alcohol-induced cerebrovascular constriction
Proc. Natl. Acad. Sci. U. S. A.
Increased large conductance calcium-activated potassium (BK) channel expression accompanied by STREX variant downregulation in the developing mouse CNS
BMC Dev. Biol.
Ca2+-activated K+ channels of the BK-type in the mouse brain
Histochem. Cell Biol.
Presynaptic Ca2+/calmodulin-dependent protein kinase II modulates neurotransmitter release by activating BK channels at Caenorhabditis elegans neuromuscular junction
J. Neurosci.
Cited by (82)
MicroRNAs in drug addiction: Current status and future perspectives
2022, Pharmacology and TherapeuticsAlcohol induced impairment/abnormalities in brain: Role of MicroRNAs
2021, NeuroToxicologyCitation Excerpt :Alcohol also upregulates the expression of miR-34a which is a pro-apoptotic miRNA (Li et al., 2011) and miR-9, the increased concentration of miR-9 in the supra-optic and striatal neuron of brain targets the calcium and voltage-gated potassium channels. ( Pietrzykowski et al., 2008; Treistman and Martin, 2009). Shrinkage of white matter and neurodegeneration in the frontal cortex has long been associated with alcoholism (Crews and Nixon, 2009).
The genetic epidemiology of substance use disorder: A review
2017, Drug and Alcohol DependenceCitation Excerpt :Studies of the effects of alcohol on miRNA expression suggest that miRNAs work in a coordinated fashion to promote drug adaptation and neuronal plasticity and that this may occur in a relatively rapid fashion. For example, miR-9 is expected to mediate alcohol-related post-transcriptional regulation of mRNA responsible for the neuronal voltage-gated potassium channel (BK) and can do so rapidly upon exposure (Pietrzykowski et al., 2008; Treistman and Martin, 2009). More specifically, mRNA encoding the BK decreased within 15 minutes of exposing rat striatal cultures to alcohol.
Differential potassium channel gene regulation in BXD mice reveals novel targets for pharmacogenetic therapies to reduce heavy alcohol drinking
2017, AlcoholCitation Excerpt :Additionally, preclinical studies have demonstrated that chronic ethanol exposure reduces the function and trafficking of KCa2 (Kcnn), KV4.2 (Kcnd2), and KV7.2 (Kcnq2) channels in the nucleus accumbens (NAc) and hippocampus (Hopf et al., 2010; McGuier et al., 2015; Mulholland, Spencer, Hu, Kroener, & Chandler, 2015; Padula et al., 2015; Spencer, Mulholland, & Chandler, 2016), and that pharmacologically enhancing KCa2 and KV7 channel function attenuated voluntary drinking in rodents (Hopf et al., 2011; Knapp, O'Malley, Datta, & Ciraulo, 2014; McGuier et al., 2015; Padula et al., 2013). Ethanol actions on voltage- and calcium-dependent KCa1.1 (Kcnma1) channels are involved in acute ethanol tolerance, dependence, and heavy ethanol consumption (Bukiya et al., 2014; Ghezzi, Pohl, Wang, & Atkinson, 2010; Kreifeldt, Le, Treistman, Koob, & Contet, 2013; Treistman & Martin, 2009), and Kcnma1 and Kcnq5 were identified as major hub genes for the acute actions of ethanol (Wolen et al., 2012). Deletion of the gene that encodes Kir3.3 channels (Kcnj9) enhanced ethanol-conditioned place preference (Tipps, Raybuck, Kozell, Lattal, & Buck, 2016) and blunted ethanol-induced excitation of dopamine neurons and increased binge-like ethanol consumption in mice in both a limited-access 2-bottle choice (LA-2BC) model (15% v/v ethanol vs. water) and with limited access to a single bottle of 20% v/v ethanol (Herman et al., 2015).