Behavioral and Genetic Evidence for GIRK Channels in the CNS

Mayfield, Jody; Blednov, Yuri A.; Harris, R. Adron

doi:10.1016/bs.irn.2015.05.016

Cited by 48 publications

(19 citation statements)

References 136 publications

(192 reference statements)

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“…Originally implicated for their role in epilepsy (Maljevic & Lerche, 2014; Smets et al, 2015), studies show that calcium-activated (K Ca ), voltage-dependent (K V ), and G protein-coupled inwardly-rectifying (K ir ) K + channels are targets for both acute and chronic effects of ethanol (Hopf et al, 2011; Mayfield, Blednov, & Harris, 2015; Mulholland, 2012; Mulholland, Hopf, et al, 2009). Additionally, preclinical studies have demonstrated that chronic ethanol reduces the function and trafficking of K Ca 2 ( Kcnn ), K V 4.2 ( Kcnd2 ), and K V 7.2 ( 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, In Press), and pharmacologically enhancing K Ca 2 and K V 7 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).…”

Section: Introductionmentioning

confidence: 99%

Differential potassium channel gene regulation in BXD mice reveals novel targets for pharmacogenetic therapies to reduce heavy alcohol drinking

Rinker

Fulmer

Trantham-Davidson

et al. 2017

Alcohol

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Alcohol (ethanol) dependence is a chronic relapsing brain disorder partially influenced by genetics and characterized by an inability to regulate harmful levels of drinking. Emerging evidence has linked genes that encode KV7, KIR, and KCa2 K+ channels with variation in alcohol-related behaviors in rodents and humans. This led us to experimentally test relations between K+ channel genes and escalation of drinking in a chronic intermittent ethanol (CIE) exposure model of dependence in BXD recombinant inbred strains of mice. Transcript levels for K+ channel genes in the prefrontal cortex (PFC) and nucleus accumbens (NAc) covary with voluntary ethanol drinking in a non-dependent cohort. Transcripts that encode KV7 channels covary negatively with drinking in non-dependent BXD strains. Using a pharmacological approach to validate the genetic findings, C57BL/6J mice were allowed intermittent access to ethanol to establish baseline consumption before they were treated with retigabine, an FDA-approved KV7 channel positive modulator. Systemic administration significantly reduced drinking, and consistent with previous evidence, retigabine was more effective at reducing voluntary consumption in high-drinking than low-drinking subjects. We evaluated the specific K+ channel genes that were most sensitive to CIE exposure and identified a gene subset in the NAc and PFC dysregulated in the alcohol-dependent BXD cohort. CIE-induced modulation of nine genes in the NAc and six genes in the PFC covaried well with the changes in drinking induced by ethanol dependence. Here we identified novel candidate genes in the NAc and PFC that are regulated by ethanol dependence and correlate with voluntary drinking in non-dependent and dependent BXD mice. The findings that Kcnq expression correlate with drinking and that retigabine reduces consumption suggest that KV7 channels could be pharmacogenetic targets to treat individuals with alcohol addiction.

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Section: Introductionmentioning

confidence: 99%

Differential potassium channel gene regulation in BXD mice reveals novel targets for pharmacogenetic therapies to reduce heavy alcohol drinking

Rinker

Fulmer

Trantham-Davidson

et al. 2017

Alcohol

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“…G protein–gated inwardly rectifying potassium (GIRK or Kir3) channels are expressed in various regions of the brain, where they control the resting membrane potential and excitability of neurons ( Lüscher and Slesinger, 2010 ). Mouse and human molecular genetic studies have indicated a role for GIRK channels in a variety of human disorders, including addiction, alcoholism, Down’s syndrome, and depression (for a review, see Mayfield et al, 2015 ). Similar to other inwardly rectifying potassium channels, activation of GIRK channels hyperpolarizes the membrane potential, reducing neuronal excitability.…”

Section: Introductionmentioning

confidence: 99%

Dynamic role of the tether helix in PIP2-dependent gating of a G protein–gated potassium channel

Lacin

Aryal

Glaaser

et al. 2017

Journal of General Physiology

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“…Genetic evidence from mouse models has provided extensive insight into the significance of GIRK channels in drug addiction, and their role in responses to ethanol and other drugs of abuse is reviewed in (Bodhinathan & Slesinger, 2014) and (Mayfield, Blednov, & Harris, 2015). …”

Section: Ion Channelsmentioning

confidence: 99%

Genes and Alcohol Consumption

Mayfield

Arends

Harris

et al. 2016

International Review of Neurobiology

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In this chapter, we review the effects of global null mutant and overexpressing transgenic mouse lines on voluntary self-administration of alcohol. We examine approximately 200 publications pertaining to the effects of 155 mouse genes on alcohol consumption in different drinking models. The targeted genes vary in function and include neurotransmitter, ion channel, neuroimmune, and neuropeptide signaling systems. The alcohol self-administration models include operant conditioning, two- and four-bottle choice continuous and intermittent access, drinking in the dark limited access, chronic intermittent ethanol, and scheduled high alcohol consumption tests. Comparisons of different drinking models using the same mutant mice are potentially the most informative, and we will highlight those examples. More mutants have been tested for continuous two-bottle choice consumption than any other test; of the 137 mouse genes examined using this model, 97 (72%) altered drinking in at least one sex. Overall, the effects of genetic manipulations on alcohol drinking often depend on the sex of the mice, alcohol concentration and time of access, genetic background, as well as the drinking test.

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Behavioral and Genetic Evidence for GIRK Channels in the CNS

Cited by 48 publications

References 136 publications

Differential potassium channel gene regulation in BXD mice reveals novel targets for pharmacogenetic therapies to reduce heavy alcohol drinking

Differential potassium channel gene regulation in BXD mice reveals novel targets for pharmacogenetic therapies to reduce heavy alcohol drinking

Dynamic role of the tether helix in PIP2-dependent gating of a G protein–gated potassium channel

Genes and Alcohol Consumption

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