The Hormonal Control of Uterine Luminal Fluid Secretion and Absorption |
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Authors: | N?Salleh DL?Baines RJ?Naftalin Email author" target="_blank">SR?MilliganEmail author |
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Institution: | (1) Division of Molecular Bioscience, The John Curtin School of Medical Research, The Australian National University, Canberra, 2601, Australia;(2) St Vincents Institute of Medical Research, Victoria, 3065, Australia |
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Abstract: | GABAA receptors composed of α, β and γ subunits display a significantly higher single-channel conductance than receptors comprised
of only α and β subunits. The pore of GABAA receptors is lined by the second transmembrane region from each of its five subunits and includes conserved threonines at
the 6′, 10′ and 13′ positions. At the 2′ position, however, a polar residue is present in the γ subunit but not the α or β
subunits. As residues at the 2′, 6′ and 10′ positions are exposed in the open channel and as such polar channel-lining residues
may interact with permeant ions by substituting for water interactions, we compared both the single-channel conductance and
the kinetic properties of wild-type α1β1 and α1β1γ2S receptors with two mutant receptors, αβγ(S2′A) and αβγ(S2′V). We found
that the single-channel conductance of both mutant αβγ receptors was significantly decreased with respect to wild-type αβγ,
with the presence of the larger valine side chain having the greatest effect. However, the conductance of the mutant αβγ receptors
remained larger than wild-type αβ channels. This reduction in the conductance of mutant αβγ receptors was observed at depolarized
potentials only (ECl = −1.8 mV), which revealed an asymmetry in the ion conduction pathway mediated by the γ2′ residue. The substitutions at the
γ2′ serine residue also altered the gating properties of the channel in addition to the effects on the conductance with the
open probability of the mutant channels being decreased while the mean open time increased. The data presented in this study
show that residues at the 2′ position in M2 of the γ subunit affects both single-channel conductance and receptor kinetics. |
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Keywords: | GABA Single-channel Conductance Gating Kinetics Gamma subunit |
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