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

Robert J. Brosnan, Trung L. Pham

NMDA 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. Glycine 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. Ion 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. Water 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.