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The Journal of Neuroscience, February 1, 2000, 20(3):899-907
Effects of Halothane on GABAA Receptor Kinetics:
Evidence for Slowed Agonist Unbinding
Xiaoshen
Li1 and
Robert
A.
Pearce2
Departments of 1 Zoology and
2 Anesthesiology and Anatomy, University of
Wisconsin-Madison, Madison, Wisconsin 53706
Many anesthetics, including the volatile agent halothane, prolong
the decay of GABAA receptor-mediated IPSCs at central
synapses. This effect is thought to be a major factor in the production of anesthesia. A variety of different kinetic mechanisms have been
proposed for several intravenous agents, but for volatile agents the
kinetic mechanisms underlying this change remain unknown. To address
this question, we used rapid solution exchange techniques to apply GABA
to recombinant GABAA receptors
( 1 2 2s) expressed in
HEK 293 cells, in the absence and presence of halothane. To differentiate between different microscopic kinetic steps that may be
altered by the anesthetic, we studied a variety of measures, including
peak concentration-response characteristics, macroscopic desensitization, recovery from desensitization, maximal current activation rates, and responses to the low-affinity agonist taurine. Experimentally observed alterations were compared with predictions based on a kinetic scheme that incorporated two agonist binding steps,
and open and desensitized states. We found that, in addition to slowing
deactivation after a brief pulse of GABA, halothane increased agonist
sensitivity and slowed recovery from desensitization but did not alter
macroscopic desensitization or maximal activation rate and only
slightly slowed rapid deactivation after taurine application. This
pattern of responses was found to be consistent with a reduction in the
microscopic agonist unbinding rate
(koff) but not with changes in
channel gating steps, such as the channel opening rate (), closing
rate (), or microscopic desensitization. We conclude that halothane
slows IPSC decay by slowing dissociation of agonist from the receptor.
Key words:
GABA; halothane; taurine; synaptic inhibition; anesthetics; receptor kinetics
Copyright © 2000 Society for Neuroscience 0270-6474/00/203899-09$05.00/0
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