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

  • Alex M. DopicoEmail author
  • Anna N. Bukiya
  • Jill C. Bettinger
Chapter
Part of the Handbook of Experimental Pharmacology book series (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.

Keywords

Alcohol KCNMB genes MaxiK channel Neuron Slo1 and orthologs 

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

Notes

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

  • Alex M. Dopico
    • 1
    Email author
  • Anna N. Bukiya
    • 1
  • Jill C. Bettinger
    • 2
  1. 1.Department of PharmacologyCollege of Medicine, The University of Tennessee Health Science CenterMemphisUSA
  2. 2.Department of Pharmacology and ToxicologyVirginia Commonwealth UniversityRichmondUSA

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