Nature Neuroscience
2, 226 - 233 (1999)
doi:10.1038/6326
Acetylcholine receptor M3 domain: stereochemical and volume contributions
to channel gatingHai-Long Wang1, Margherita Milone3, Kinji Ohno2, Xing-Ming Shen2, Akira Tsujino2, Anna Paola Batocchi3, Pietro Tonali3, Joan Brengman2, Andrew G. Engel2
& Steven M. Sine11
Receptor Biology Laboratory, Department of Physiology
and Biophysics, Rochester, Minnesota 55905
, USA
2
Muscle Research Laboratory, Department of Neurology,
Mayo Foundation, Rochester, Minnesota 55905
, USA
3
Department of Neurology, Catholic University of Rome
, Rome, Italy
Correspondence should be addressed to Steven M. Sine sine@mayo.eduBy defining the functional defect in a congenital myasthenic syndrome (CMS),
we show that the third transmembrane domain (M3) of the muscle acetylcholine
receptor governs the speed and efficiency of gating of its channel. The clinical
phenotype of this CMS results from the mutation V285I in M3 of the 
subunit, which attenuates endplate currents, accelerates their decay and causes
abnormally brief acetylcholine-induced single-channel currents. Kinetic analysis
of engineered V285I receptors demonstrated a predominant effect on
channel gating, with abnormally slow opening and rapid closing rates. Analysis
of site-directed mutations revealed stereochemical and volume-dependent contributions
of V285 to channel gating. Thus, we demonstrate a functional role for
the M3 domain as a key component of the nicotinic acetylcholine receptor channel-gating
mechanism.
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