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Biophys J, April 2002, p. 1920-1929, Vol. 82, No. 4
*Instituto de Investigaciones Bioquímicas, UNS-CONICET,
Bahía Blanca, Argentina; and Receptor Biology
Laboratory, Department of Physiology and Biophysics, Mayo
Foundation, Rochester, MN, USA
The muscle nicotinic receptor (AChR) is a pentamer of
four different subunits, each of which contains four transmembrane
domains (M1-M4). We recently showed that channel opening and closing
rates of the AChR depend on a hydrogen bond involving a threonine at position 14' of the M4 domain in the 
-subunit. To determine whether residues in equivalent positions in non--subunits contribute to
channel gating, we mutated 
T14', 
T14', and 
S14' and evaluated changes in the kinetics of acetylcholine-activated currents. The mutation S14'A profoundly slows the rate of channel closing, an
effect opposite to that produced by mutation of T14'. Unlike mutations of T14', S14'A does not affect the rate of channel opening. Mutations in T14' and T14' do not affect channel opening or closing kinetics, showing that conserved residues are not
functionally equivalent in all subunits. Whereas T14'A and S14'A
subunits contribute additively to the closing rate, they contribute
nonadditively to the opening rate. Substitution of residues preserving
the hydrogen bonding ability at position 14' produce nearly normal
gating kinetics. Thus, we identify subunit-specific contributions to
channel gating of equivalent residues in M4 and elucidate the
underlying mechanistic and structural bases.
Biophys J, April 2002, p. 1920-1929, Vol. 82, No. 4
© 2002 by the Biophysical Society 0006-3495/02/04/1920/10 $2.00
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