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
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