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The Journal of Neuroscience, September 15, 2002, 22(18):7982-7990
Desensitization Mechanism of GABA Receptors Revealed by Single
Oocyte Binding and Receptor Function
YongChang
Chang,
Emmanuel
Ghansah,
Yonghui
Chen,
Jiawei
Ye, and
David S.
Weiss
Departments of Neurobiology and Physiology, and Biophysics,
University of Alabama at Birmingham, Birmingham, Alabama 35294
Prolonged exposure of most fast neurotransmitter-operated ion
channels to agonist drives the receptors into a nonfunctional, or
desensitized, state. Despite extensive investigation, desensitization remains a thoroughly characterized, yet poorly understood, process. Part of the difficulty in elucidating the mechanism of desensitization has been an inability to resolve the kinetics of both agonist binding
and functional desensitization in the same set of operable receptors.
To overcome this limitation, we applied single oocyte 3H-ligand binding and two-electrode voltage clamp to
oocytes expressing recombinant  1 2 2 GABA receptors. Using this
approach, we report several observations fundamental to the mechanism
of desensitization. First, we confirm that desensitization reversibly
shifts GABA receptors into a high-affinity state. For
[3H]GABA binding, the half-maximal binding of the
desensitized state was ~0.040 µM. Second, we
show that, upon agonist removal, this high-affinity state disappears
with a time constant of 127 ± 12 sec (n = 4),
similar to the time constant for functional recovery from
desensitization of 124 ± 26 sec (n = 5).
[3H]GABA, however, dissociates fourfold faster
( = 30 ± 2 sec; n = 3) than
functional recovery, indicating that desensitized receptors need not be
bound by GABA. These data provide direct evidence for a cyclical model
of receptor desensitization.
Key words:
GABAA receptor; desensitization; binding; kinetics; affinity; oocyte
Copyright © 2002 Society for Neuroscience 0270-6474/02/22187982-09$05.00/0
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