Emerging Concepts in Ion Channel Biophysics

Emerging Concepts in Ion Channel Biophysics

Wednesday Speaker Abstracts

Binding of General Anesthetics to Ion Channels

Werner Treptow

Universidade de Brasilia, Brasilia, Brazil.

How anesthetics modulate ion-channel to account for endpoints of anesthesia has been reasoned

in terms of two competing hypotheses. The first view points that indirect effects resulting from

anesthetic partition into the membrane impact channel energetics and conductance to induce

anesthesia. Alternatively, the site-direct hypothesis states that anesthetics bind channel receptors

to affect protein equilibrium and function. Here, we have explored such hypotheses to study the

haloether sevoflurane and its interaction to the well-understood resting-closed (R) and activated-

open (A) structures of the mammalian voltage-gated potassium channel Kv1.2. Recent studies

support that sevoflurane potentiates Kv1.2 in a dose-dependent manner shifting the open

probability (PO) of the channel and increasing conductance. Accordingly, we have worked

specifically at the theoretical reconstruction of PO curves of Kv1.2 by embodying the (i)

modulation of the channel energetics by sevoflurane-induced changes of membrane lateral

pressure and (ii) ligand binding. Extensive MD-simulations of the membrane-embedded R and A

structures in presence of sevoflurane show spontaneous partition of the ligand in the lipid

bilayer. Despite changes of membrane order parameters and lateral pressure, partition of

sevoflurane was found to moderately impact PO curves as a result of minimal molecular

reshaping between Kv structures. Contrasting the membrane-mediated results, molecular binding

of sevoflurane to Kv structures was found to shift the voltage-dependence of the channel in

agreement to measurements. Specifically, extensive docking and free-energy calculations show

that sevoflurane binds structures R and A through multiple sites. Despite a similar interaction

pattern against Kv structures, site-specific binding of sevoflurane is conformation dependent

accounting for considerable shifts of channel equilibrium. The result is promising as the

necessary condition to look forward for mechanistic explanations of anesthetic action involving

direct interactions to specific ion channels in detriment of alternative mechanisms.