Exploring the mechanism of general anesthesia: kinetic analysis of GABAA receptor electrophysiology.

Abstract:

:A kinetic model of the effect of agonist and anesthetics on ligand-gated ion channels, developed in earlier work, is further refined and used to predict traces observed in fast-perfusion electrophysiological studies on recombinant GABAA receptors under a wide range of agonist and/or anesthetic concentrations. The model incorporates only three conformational states (resting, open, and desensitized) but allows for the modulation of the conformational free energy landscape connecting these states resulting from adsorption of agonist and/or anesthetic to the bilayer in which the protein is embedded. The model is shown to reproduce the diverse and complex features of experimental traces remarkably well, including both anesthetic-induced and agonist-induced traces, as well as the modulation of agonist-induced traces by anesthetic, either coapplied or continuously present. The solutions to the kinetic equations, which give the time-dependence of each of the nine protein states (three ligation states for each of the three conformations), describe the flow of probability among these states and thus reveal the kinetic underpinnings of the traces. Many of the parameters in the model, such as the desorption rate constants of anesthetic and agonist, are directly related to model-independent experimental measurements and thus can serve as a definitive test of its validity.

journal_name

Biophys J

journal_title

Biophysical journal

authors

Lee DK,Albershardt DJ,Cantor RS

doi

10.1016/j.bpj.2014.12.052

subject

Has Abstract

pub_date

2015-03-10 00:00:00

pages

1081-93

issue

5

eissn

0006-3495

issn

1542-0086

pii

S0006-3495(15)00060-0

journal_volume

108

pub_type

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