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Vol. 55, Issue 2, 386-395, February 1999
School of Physiology and Pharmacology, University of New South
Wales, Sydney, Australia (A.J.M., P.H.B.) and
The Garvan Institute of
Medical Research, Darlinghurst, Sydney, Australia (P.J., P.R.S.)
Hyperekplexia (startle disease) results from mutations in the glycine
receptor chloride channel that disrupt inhibitory synaptic transmission. The Q266H missense mutation is the only hyperekplexia mutation located in the transmembrane domains of the receptor. Using
recombinant expression and patch-clamping techniques, we have
investigated the functional properties of this mutation. The ability of
glycine and taurine to open the channel was reduced in the mutated
channel, as shown by a 6-fold shift in the concentration-response curve
for both agonists. This was not accompanied by similar changes in
agonist displacement of strychnine binding, suggesting that the
mutation affects functions subsequent to ligand binding. Taurine was
also converted to a weak partial agonist and antagonized the actions of
glycine, consistent with changes in its channel gating efficacy.
Because the Q266H mutation is within the pore-forming second
transmembrane domain, we tested for a direct interaction with
permeating ions. No change in either the cation/anion selectivity ratio
or in single channel conductance levels was observed. No differential
effects of Zn++, pH, and diethylpyrocarbonate were
observed, implying that the histidine side chain is not exposed to the
channel lumen. Single-channel recordings revealed a significant
reduction in open times in the mutant receptors, at both high and low
agonist concentrations, consistent with the open state of the channel
being less stable. This study demonstrates that residues within the
second transmembrane domain of ligand-gated ion channel receptors, even
those whose side chains do not directly interact with permeating ions,
can affect the kinetics of channel gating.
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