Abstract
BackgroundMany anesthetics modulate 3-transmembrane (such as NMDA) and 4-transmembrane (such as GABAA) receptors. Clinical and experimental anesthetics exhibiting receptor family specificity often have low water solubility. We hypothesized that the molar water solubility of a hydrocarbon could be used to predict receptor modulation in vitro.MethodsGABAA (α1β2γ2s) or NMDA (NR1/NR2A) receptors were expressed in oocytes and studied using standard two-electrode voltage clamp techniques. Hydrocarbons from 14 different organic functional groups were studied at saturated concentrations, and compounds within each group differed only by the carbon number at the ω-position or within a saturated ring. An effect on GABAA or NMDA receptors was defined as a 10% or greater reversible current change from baseline that was statistically different from zero.ResultsHydrocarbon moieties potentiated GABAA and inhibited NMDA receptor currents with at least some members from each functional group modulating both receptor types. A water solubility cut-off for NMDA receptors occurred at 1.1 mM with a 95% CI = 0.45 to 2.8 mM. NMDA receptor cut-off effects were not well correlated with hydrocarbon chain length or molecular volume. No cut-off was observed for GABAA receptors within the solubility range of hydrocarbons studied.ConclusionsHydrocarbon modulation of NMDA receptor function exhibits a molar water solubility cut-off. Differences between unrelated receptor cut-off values suggest that the number, affinity, or efficacy of protein-hydrocarbon interactions at these sites likely differ.
Highlights
Many anesthetics modulate 3-transmembrane and 4-transmembrane receptors
With the exception of the aldehydes, alkynes, and cycloalkanes, GABAA receptor inhibition tended to decrease with increasing hydrocarbon chain length
No water solubility cut-off effect was observed for GABAA receptors for the compounds tested
Summary
Many anesthetics modulate 3-transmembrane (such as NMDA) and 4-transmembrane (such as GABAA) receptors. Inhaled anesthetics interact with putative cell receptor targets in a manner uncharacteristic of most other pharmacologic agents. They exhibit immobilization efficacy in all animals, both vertebrates and invertebrates, and even in protozoa and plants. Within the NMDA and GABAA channel proteins, hydrophilic or amphipathic cavities or pockets have been postulated near the solvent interface and within transmembrane segments of several subunits [7,8] Such cavities might conceivably contain solvent molecules or nothing at all, though it should be thermodynamically less favorable to maintain a vacuum within a pocket that is sufficiently large and polar enough to accommodate water
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