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Anesthetic-sensitive ion channel modulation is associated with a molar water solubility cut-off.
Brosnan RJ
,
Pham TL
.
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BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
Fig 1.
Sample tracings for (a) Nav1.2 channels, (b) TREK-1 channels, and (c) glycine receptors before and after alcohol exposure at saturated aqueous phase concentrations (Table 1). Whole cell current responses were qualitatively similar between both Nav channels and between both K2P channels. Electrophysiologic responses of GABAA receptors during similar hydrocarbon exposure studies have been published elsewhere [6, 7]
Fig 2.
Summary of ion channel response as a function of hydrocarbon molar water solubility. Hydrocarbons that modulate ion channel function are indicated by a white bar. Hydrocarbons that did not affect whole cell currents for an ion channel are indicated by a black bar. The grey bar represents the 95% confidence interval around the mean hydrocarbon molar water solubility cut-off value for each ion channel
Fig 3.
GABAA receptor current potentiation (white bars) and absent whole cell current effects for eight different organic classes graphed as a function of the calculated hydrocarbon molar water solubility. The grey bars represent hydrocarbon solubility ranges within each organic class for which GABAA receptor modulation was not evaluated. Cut-off values are clustered between 6.0 × 10− 5 and 2.5 × 10− 4 M
Fig 4.
Graph of GABAA receptor modulation as a function of the number of carbon atoms in a molecule (Panel a) and as a function of hydrocarbon molecular volume (Panel b). White and black bars indicate carbon numbers (Panel a) and molecular volumes (Panel b) associated with receptor potentiation and absent receptor modulation, respectively. Grey bars indicate regions for which hydrocarbon response data is not available. No pattern of consistent cut-off values associated with hydrocarbon chain length or molecular volume is evident
Fig. 1. Sample tracings for (a) Nav1.2 channels, (b) TREK-1 channels, and (c) glycine receptors before and after alcohol exposure at saturated aqueous phase concentrations (Table 1). Whole cell current responses were qualitatively similar between both Nav channels and between both K2P channels. Electrophysiologic responses of GABAA receptors during similar hydrocarbon exposure studies have been published elsewhere [6, 7]
Fig. 2. Summary of ion channel response as a function of hydrocarbon molar water solubility. Hydrocarbons that modulate ion channel function are indicated by a white bar. Hydrocarbons that did not affect whole cell currents for an ion channel are indicated by a black bar. The grey bar represents the 95% confidence interval around the mean hydrocarbon molar water solubility cut-off value for each ion channel
Fig. 3. GABAA receptor current potentiation (white bars) and absent whole cell current effects for eight different organic classes graphed as a function of the calculated hydrocarbon molar water solubility. The grey bars represent hydrocarbon solubility ranges within each organic class for which GABAA receptor modulation was not evaluated. Cut-off values are clustered between 6.0 × 10− 5 and 2.5 × 10− 4 M
Fig. 4. Graph of GABAA receptor modulation as a function of the number of carbon atoms in a molecule (Panel a) and as a function of hydrocarbon molecular volume (Panel b). White and black bars indicate carbon numbers (Panel a) and molecular volumes (Panel b) associated with receptor potentiation and absent receptor modulation, respectively. Grey bars indicate regions for which hydrocarbon response data is not available. No pattern of consistent cut-off values associated with hydrocarbon chain length or molecular volume is evident
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