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J Neurosci. 2000 Feb 1;20(3):899-907.

Effects of halothane on GABA(A) receptor kinetics: evidence for slowed agonist unbinding.

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  • 1Department of Zoology, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.

Abstract

Many anesthetics, including the volatile agent halothane, prolong the decay of GABA(A) 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 GABA(A) receptors (alpha(1)beta(2)gamma(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 (k(off)) but not with changes in channel gating steps, such as the channel opening rate (beta), closing rate (alpha), or microscopic desensitization. We conclude that halothane slows IPSC decay by slowing dissociation of agonist from the receptor.

PMID:
10648694
[PubMed - indexed for MEDLINE]
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