Open AccessAlcohol reduces muscle fatigue through atomistic interactions with nicotinic receptors
Author(s) -
Hamid Noori,
Christian Mücksch,
Valentina Vengeliene,
Kai Shi,
Tatiane T. Takahashi,
Nuriya Mukhtasimova,
Maryam Bagher Oskouei,
Matías Mosqueira,
Dušan Bartsch,
Rainer H. A. Fink,
Herbert M. Urbassek,
Rainer Spanagel,
Steven M. Sine
Publication year - 2018
Publication title -
communications biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.812
H-Index - 26
ISSN - 2399-3642
DOI - 10.1038/s42003-018-0157-9
Subject(s) - acetylcholine receptor , nicotinic agonist , biophysics , skeletal muscle , nicotinic acetylcholine receptor , chemistry , ethanol , acetylcholine , mutant , amino acid , molecular dynamics , receptor , in vivo , ion channel , biochemistry , pharmacology , biology , endocrinology , genetics , gene , computational chemistry
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.