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.

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