TY - JOUR
T1 - Alcohol reduces muscle fatigue through atomistic interactions with nicotinic receptors
AU - Noori, Hamid R.
AU - Mücksch, Christian
AU - Vengeliene, Valentina
AU - Schönig, Kai
AU - Takahashi, Tatiane T.
AU - Mukhtasimova, Nuriya
AU - Bagher Oskouei, Maryam
AU - Mosqueira, Matias
AU - Bartsch, Dusan
AU - Fink, Rainer
AU - Urbassek, Herbert M.
AU - Spanagel, Rainer
AU - Sine, Steven M.
N1 - Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s42003-018-0157-9
DO - 10.1038/s42003-018-0157-9
M3 - Article
C2 - 30302403
AN - SCOPUS:85071045943
SN - 2399-3642
VL - 1
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 159
ER -