Understanding Anesthetic Mechanisms: Analysis of the Complex Kinetics of Ligand-Gated Ion Channels.

Anesthetics modulate the response of ligand-gated ion channels to their neurotransmitter agonists, in a way that is consistent with clinical anesthesia: inhibition of synaptic transmission, by activation of inhibitory receptors and/or inhibition of excitatory receptors. Electrophysiological results for receptors such as GABAR indicate that this modulation can be remarkably kinetically complex, characterized by concentration-dependent changes in the extent and (multiple) time scales of desensitization and deactivation. The full range of these features cannot be reproduced by a kinetic model in which anesthetic acts only by binding to putative protein sites, without having multiple sites with varying affinities, as well as many additional conformational states beyond the canonical set of three (resting, open, and desensitized). So, we discuss the implementation of a kinetic approach that incorporates only these three states, but accounts for effects of adsorption of anesthetic and agonist to the membrane in which the receptor is embedded, which modulates the conformational free energy landscape of the protein. As a result, the rate constants of conformational transitions become time dependent (non-Markovian), requiring nonstandard methods of kinetic analysis that can readily be implemented using available computational software.