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A Molecular Target for an Alcohol Chain-Length Cutoff
Hae-Won Chung1, E Nicholas Petersen1, Cerrone Cabanos1
1Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL 33458, USA; Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
Journal of Molecular Biology
|December 12, 2018
Summary
Phospholipase D (PLD) generates alcohol metabolites that affect potassium channels, explaining the alcohol chain-length cutoff effect. Loss of PLD blocks alcohol-induced hyperactivity in fruit flies, revealing PLD
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Mechanisms of ethanol anesthesia are not fully understood.
- The "chain-length cutoff effect" describes how alcohol potency diminishes beyond a certain molecular size.
- Previous research suggested alcohol binding sites on proteins, but their specific location and function in the cutoff effect remained unclear.
Purpose of the Study:
- To investigate the role of phospholipase D (PLD) in mediating behavioral responses to alcohol.
- To elucidate the molecular mechanisms underlying the alcohol chain-length cutoff effect.
- To identify the specific molecular targets and pathways involved in alcohol's anesthetic action.
Main Methods:
- Utilized Drosophila melanogaster (fruit fly) as a model organism.
- Examined the behavioral effects of ethanol in fruit flies with and without functional PLD.
- Investigated the interaction of alcohol metabolites with lipid-binding sites in potassium channels, specifically TREK-1.
Main Results:
- Loss of phospholipase D (PLD) function abolished ethanol-mediated hyperactivity in fruit flies.
- The PLD metabolite phosphatidylethanol was found to directly compete with phosphatidic acid for binding sites on TREK-1 potassium channels.
- This competition resulted in a PLD-dependent cutoff effect observed in TREK-1 channel activity.
Conclusions:
- Phospholipase D (PLD) plays a crucial role in mediating behavioral responses to alcohol in vivo.
- Alcohol metabolites produced by PLD act on lipid-regulated potassium channels, explaining the chain-length cutoff effect.
- A novel alcohol pathway involving PLD, its metabolites, and potassium channels is proposed to regulate downstream effectors.
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