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Vol. 53, Issue 3, 511-523, March 1998
1 
-Aminobutyric Acid Receptors
Departments of Neurobiology and Physiology & Biophysics, University
of Alabama at Birmingham, Birmingham, Alabama 35294
All members of the receptor-operated ion channel family that includes
-aminobutyric acid (GABA), glycine, nicotinic acetylcholine, and
serotonin type 3 receptors have a conserved leucine near the center of
the presumed second membrane-spanning domain. This leucine has been
postulated to play a role in the gating of the pore. In this study, we
examined the effects of mutating this leucine (L301) on the function of
human homomeric 
1 GABA receptors. Oocytes expressing 1 GABA
receptors in which this leucine was substituted with alanine (A),
glycine (G), serine (S), threonine (T), valine, or tyrosine, but not
isoleucine or phenylalanine, demonstrated larger-than-normal resting
conductances in the absence of GABA. This resting conductance had a
reversal potential (and shifted reversal potential with chloride
substitution) indistinguishable from that of the wild-type 1
GABA-activated current. This resting conductance was antagonized by
picrotoxin and, in the case of the A, G, S, and T substitutions, by
GABA itself. Although the 1 competitive antagonist
3-aminopropyl(methyl)-phosphinic acid did not block the resting
conductance, this compound did competitively inhibit the GABA-mediated
antagonism of the resting conductance. At higher concentrations, both
3-aminopropyl(methyl)-phosphinic acid and GABA directly activated the
A, G, S, and T mutant receptors. Taken together, these data suggest
that substitution of this highly conserved leucine with either small or
polar residues produced 1 GABA receptors that can open in the
absence of GABA and support the hypothesis that this leucine may play a
key role in the gating of the pore.
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