Anesthetic-sensitive ion channel modulation is associated with a molar water solubility cut-off

Robert J Brosnan,Trung L Pham

doi:10.1186/s40360-018-0244-z

Abstract

BackgroundNMDA receptor modulation by hydrocarbons is associated with a molar water solubility cut-off. Low-affinity phenolic modulation of GABAA receptors is also associated with a cut-off, but at much lower molar solubility values. We hypothesized that other anesthetic-sensitive ion channels exhibit distinct cut-off effects associated with hydrocarbon molar water solubility, and that cut-off values are comparatively similar between related receptors than phylogenetically distant ones.MethodsGlycine or GABAA receptors or TREK-1, TRESK, Nav1.2, or Nav1.4 channels were expressed separately in frog oocytes. Two electrode voltage clamp techniques were used to study current responses in the presence and absence of hydrocarbon series from eight functional groups with progressively increasing size at saturated aqueous concentrations. Null response (cut-off) was defined by current measurements that were statistically indistinguishable between baseline and hydrocarbon exposure.ResultsIon channels exhibited cut-off effects associated with hydrocarbon molar water solubility in the following order of decreasing solubility: Nav1.2 ≈ Nav1.4 ≳ TRESK ≈ TREK-1 > GABAA >> glycine. Previously measured solubility cut-off values for NMDA receptors were intermediate between those for Nav1.4 and TRESK.ConclusionsWater solubility cut-off responses were present for all anesthetic-sensitive ion channels; distinct cut-off effects may exist for all cell surface receptors that are sensitive to volatile anesthetics. Suggested is the presence of amphipathic receptor sites normally occupied by water molecules that have dissociation constants inversely related to the cut-off solubility value. Poorly soluble hydrocarbons unable to reach concentrations sufficient to out-compete water for binding site access fail to modulate the receptor.

Highlights

NMDA receptor modulation by hydrocarbons is associated with a molar water solubility cut-off
We evaluated responses of anesthetic-sensitive channels and receptors to eight different functional groups of organic compounds, differing only by carbon additions to the ω-end of a chain or to a ring, so that we could study compounds of different molecular volumes and carbon atoms but similar molar water solubility values and distinguish between effects caused by drug size versus solubility
Inhaled anesthetics bind many different proteins, we studied six channels and receptors reported to contribute to immobilizing effects in vivo: voltage-gated sodium channels type II and type IV (Nav1.2 and Nav1.4), [8] TWIK-related spinal cord channel (TRESK) [9], TWIK-related potassium channel type I (TREK-1) [10], γ-aminobutyric acid receptor type A (GABAA) receptors [11], and glycine receptors [12]

Summary

Introduction

NMDA receptor modulation by hydrocarbons is associated with a molar water solubility cut-off. A single inhaled anesthetic can allosterically modulate function of a large number of structurally diverse and phylogenetically unrelated ion channels—including many different ligand-gated ion channels, voltage-gated ion channels, and leak channels— and cell surface receptors—including many different channel-linked receptors, enzyme-linked receptors, and G protein-coupled receptors. These agents act like a key that can open many different locks

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