Anesthetic-Like Modulation of Receptor Function by Surfactants: A Test of the Interfacial Theory of Anesthesia

Abstract

Inhaled anesthetics are interfacially active, concentrating at interfaces such as the protein/water or bilayer/water interfaces. We tested the hypothesis that interfacial activity was a sufficient condition for anesthetic-like modulation of receptor function by applying surfactants to gamma-aminobutyric acid type A (GABA(A)), glycine, and N-methyl-d-aspartate (NMDA) receptors. We defined anesthetic-like modulation as an increase in currents through native channels that isoflurane and ethanol increased currents through, and a decrease in currents through channels that isoflurane and ethanol decreased currents through. We also tested the null hypothesis that there would be no difference in modulation of channel currents by surfactants in receptors with point mutations that diminished their response to isoflurane and ethanol compared to the native version of these receptors. The effect of seven surfactants with different head group charges (anionic, cationic, zwitterionic, and uncharged) and tail lengths (8 carbons and 12 carbons) on homomeric wild type alpha1 and mutant alpha(1) (S267I) glycine receptors, wild type alpha(1)beta(2)gamma(2s) and mutant alpha(1)(S270I)beta(2)gamma(2s) GABA(A) receptors, and wild type NR1/NR2A and mutant NR1(F639A)/NR2A NMDA receptors was studied. Receptors were expressed in Xenopus laevis oocytes and studied using two-electrode voltage clamping. All seven surfactants, isoflurane, and ethanol enhanced GABA(A) receptor function. Six of seven surfactants, isoflurane, and ethanol enhanced glycine receptor function. Six of seven surfactants, isoflurane, and ethanol inhibited NMDA receptor function. For the mutant receptors, five of seven surfactants increased currents through GABA(A) receptors, whereas six of seven surfactants increased currents through glycine receptors. Six of seven surfactants decreased currents through the NMDA receptor. In contrast to isoflurane and ethanol, surfactants as a group did not diminish modulation of mutant compared to wild type receptors. These findings identify another large class of compounds (surfactants) that modulate the function of GABA(A), glycine, and NMDA receptors in a manner that is qualitatively similar to inhaled anesthetics. We cannot reject the hypothesis that interfacial activity is a sufficient condition for anesthetic-like modulation of these receptors. Mutations that diminish the modulatory effect of isoflurane and ethanol did not diminish the modulatory effect of the surfactants.