Abstract
Alcohol consumption affects many organs and tissues, including skeletal muscle. However, the molecular mechanism of ethanol action on skeletal muscle remains unclear. Here, using molecular dynamics simulations and single channel recordings, we show that ethanol interacts with a negatively charged amino acid within an extracellular region of the neuromuscular nicotinic acetylcholine receptor (nAChR), thereby altering its global conformation and reducing the single channel current amplitude. Charge reversal of the negatively charged amino acid abolishes the nAChR-ethanol interaction. Moreover, using transgenic animals harboring the charge-reversal mutation, ex vivo measurements of muscle force production show that ethanol counters fatigue in wild type but not homozygous αE83K mutant animals. In accord, in vivo studies of motor coordination following ethanol administration reveal an approximately twofold improvement for wild type compared to homozygous mutant animals. Together, the converging results from molecular to animal studies suggest that ethanol counters muscle fatigue through its interaction with neuromuscular nAChRs.
Highlights
Alcohol consumption affects many organs and tissues, including skeletal muscle
Molecular docking analyses suggest that ethanol may form a hydrogen bond (H-bond) of −2.0 kcal/mol with the backbone carbonyl oxygen of the pore-residing aspartic acid α83 (Fig. 1b; Supplementary Fig. 2)
There is no direct interaction with the acidic side chain of aspartic acid its negatively charged carboxylate is necessary to induce a dipole by organizing the electron density required for building a hydrogen bond between the backbone oxygen and ethanol
Summary
Alcohol consumption affects many organs and tissues, including skeletal muscle. the molecular mechanism of ethanol action on skeletal muscle remains unclear. Using molecular dynamics simulations and single channel recordings, we show that ethanol interacts with a negatively charged amino acid within an extracellular region of the neuromuscular nicotinic acetylcholine receptor (nAChR), thereby altering its global conformation and reducing the single channel current amplitude. Using transgenic animals harboring the charge-reversal mutation, ex vivo measurements of muscle force production show that ethanol counters fatigue in wild type but not homozygous αE83K mutant animals. Following the in silico studies, we conduct single channel recordings of wild type and mutant nAChRs to evaluate the computational prediction of reduced ethanol sensitivity. Ex vivo measurements of muscle fatigue, as well as in vivo testing of motor, coordination and muscle strength, in wild type and transgenic rats, confirm the multi-scale impact of the ethanol interactions with nAChR at molecular level on muscle function in living organism
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