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Vol. 57, Issue 5, 875-882, May 2000
1 or 
1 Subunit
Produces Subunit-Specific Changes in the Function of Human
11 
-Aminobutyric AcidA
Receptors
Membrane Biology Program, John Curtin School of Medical Research,
Australian National University, Canberra, Australian Capital Territory,
Australia
The properties of the human 
1
1
-aminobutyric acid (GABA)A receptors were investigated
after mutation of a highly conserved leucine residue at the 9' position
in the second membrane-spanning region (TM2). The role of this residue
in 1 and 1 subunits was examined by
mutating the 9' leucine to phenylalanine, tyrosine, or alanine. The
mutations were in either the 1 subunit (*), the
1 subunit (*), or in both subunits
(**), and the receptors were expressed in Sf9
cells. Our results show that the rate of desensitization is increased
as the size and hydrophobicity of the 9' residue in the
1 subunit is increased: Y, F > L > A, T. Mutation of L9' in only the 1 subunit (*) to
either phenylalanine or tyrosine increased the EC50 value
for GABA at least 100 times, but the EC50 was unchanged in
* alanine mutants. In the 9' 1 mutants
(*, **) the GABA EC50 was minimally
affected. In * and **, but not *, the peak
currents evoked by millimolar concentrations of GABA were greatly
reduced. The reduction in currents could only be partially accounted
for by decreased expression of the receptors These findings suggest
different roles for the two types of subunits in GABA activation and
later desensitization of 11 receptors. In
addition, an increase in the resting membrane conductance was recorded
in alanine but not in phenylalanine and tyrosine mutants, indicating
that the side chain size at the 9' position is a major determinant of
current flow in the closed conformation.
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