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Voltage-Sensitive Potassium Channels of the BK Type and Their Coding Genes Are Alcohol Targets in Neurons

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The Neuropharmacology of Alcohol

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 248))

Abstract

Among all members of the voltage-gated, TM6 ion channel superfamily, the proteins that constitute calcium- and voltage-gated potassium channels of large conductance (BK) and their coding genes are unique for their involvement in ethanol-induced disruption of normal physiology and behavior. Moreover, in vitro studies document that BK activity is modified by ethanol with an EC50~23 mM, which is near blood alcohol levels considered legal intoxication in most states of the USA (0.08 g/dL = 17.4 mM). Following a succinct introduction to our current understanding of BK structure and function in central neurons, with a focus on neural circuits that contribute to the neurobiology of alcohol use disorders (AUD), we review the modifications in organ physiology by alcohol exposure via BK and the different molecular elements that determine the ethanol response of BK in alcohol-naïve systems, including the role of an ethanol-recognizing site in the BK-forming slo1 protein, modulation of accessory BK subunits, and their coding genes. The participation of these and additional elements in determining the response of a system or an organism to protracted ethanol exposure is consequently analyzed, with insights obtained from invertebrate and vertebrate models. Particular emphasis is put on the role of BK and coding genes in different forms of tolerance to alcohol exposure. We finally discuss genetic results on BK obtained in invertebrate organisms and rodents in light of possible extrapolation to human AUD.

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Notes

  1. 1.

    As previously discussed (Dopico et al. 2014), “BK channel” should properly be used to denominate not only Ca2+ i-activated K+ channels of large conductance, which are products of the Slo1 gene (slo1 channels) and orthologs, but also the products of Slo2 and Slo3 genes, which render K+ channels gated by ions other than Ca2+. Thus, slo1 channels should be labeled \( {\mathrm{BK}}_{\mathrm{V},{\mathrm{Ca}}^{2+}} \). For consistency with most of the literature and brevity, we will simply use the term “BK” to design a protein complex (with or without regulatory subunits) where the channel-forming subunits are slo1 proteins.

  2. 2.

    Unless otherwise stated, statements in this chapter refer to findings obtained in rat or mouse brain and neurons.

Abbreviations

ACA:

Acetaldehyde

AFT:

Acute functional tolerance

AHP:

Afterhyperpolarization

AMPA:

2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid

AP:

Action potential

AUD:

Alcohol use disorders

BK:

Voltage- and calcium-gated potassium channel of large conductance

CaV :

Voltage-gated calcium channel

CIE:

Chronic intermittent ethanol

cPC:

Cerebellar Purkinje cell

CTD:

Cytosolic tail domain

DA:

Dopamine

EC:

Extracellular

EC50 :

Ligand concentration at which 50% of the ligand’s maximal effect is reached

fAHP:

Fast afterhyperpolarization

GABA:

4-Aminobutanoic acid

GLUT:

Glutamate

HIC:

Handling-induced convulsions

I:

Macroscopic current

i/IC:

Intracellular

Ibtx:

Iberiotoxin

KO:

Knockout

KV :

Voltage-gated potassium channel

LORR:

Loss of righting reflex

MSN:

Medium spiny neuron

NMDA:

N-methyl-d-aspartate

PGD:

Pore-gate domain

PKA:

Protein kinase A

Po:

Open probability

POPE:

1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine

RCK:

Regulatory of conductance for potassium

SCN:

Suprachiasmatic neurons

SN:

Substantia nigra

TM:

Transmembrane

VSD:

Voltage-sensor domain

VTA:

Ventro-tegmental area

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Acknowledgments

This work was supported by the National Institute of Alcohol Abuse and Alcoholism through grants R37-AA11560 (AD), R01 AA-023764 (AB), and R01 AA-024482 (JB).

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Authors and Affiliations

  1. Department of Pharmacology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA

    Alex M. Dopico & Anna N. Bukiya

  2. Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA

    Jill C. Bettinger

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  1. Alex M. Dopico
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  2. Anna N. Bukiya
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  3. Jill C. Bettinger
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Correspondence to Alex M. Dopico .

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Editors and Affiliations

  1. Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA

    Kathleen A. Grant

  2. Laboratory for Integrative Neuroscience, National Institutes of Health, Bethesda, MD, USA

    David M. Lovinger

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Dopico, A.M., Bukiya, A.N., Bettinger, J.C. (2017). Voltage-Sensitive Potassium Channels of the BK Type and Their Coding Genes Are Alcohol Targets in Neurons. In: Grant, K., Lovinger, D. (eds) The Neuropharmacology of Alcohol . Handbook of Experimental Pharmacology, vol 248. Springer, Cham. https://doi.org/10.1007/164_2017_78

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