Assessing anesthetic activity through modulation of the membrane dipole potential

Abstract

There is great individual variation in response to general anesthetics (GAs) leading to difficulties in optimal dosing and sometimes even accidental awareness during general anesthesia (AAGA). AAGA is a rare, but potentially devastating, complication affecting between 0.1% and 2% of patients undergoing surgery. The development of novel personalized screening techniques to accurately predict a patient’s response to GAs and the risk of AAGA remains an unmet clinical need. In the present study, we demonstrate the principle of using a fluorescent reporter of the membrane dipole potential, di-8-ANEPPs, as a novel method to monitor anesthetic activity using a well-described inducer/noninducer pair. The membrane dipole potential has previously been suggested to contribute a novel mechanism of anesthetic action. We show that the fluorescence ratio of di-8-ANEPPs changed in response to physiological concentrations of the anesthetic, 1-chloro-1,2,2-trifluorocyclobutane (F3), but not the structurally similar noninducer, 1,2-dichlorohexafluorocyclobutane (F6), to artificial membranes and in vitro retinal cell systems. Modulation of the membrane dipole provides an explanation to overcome the limitations associated with the alternative membrane-mediated mechanisms of GA action. Furthermore, by combining this technique with noninvasive retinal imaging technologies, we propose that this technique could provide a novel and noninvasive technique to monitor GA susceptibility and identify patients at risk of AAGA.

Effect of Local Anesthetics on the Organization and Dynamics of Hippocampal Membranes: A Fluorescence Approach

“…The figure shows a reduction in R of ∼16% at the highest concentration of PEtOH used. Although general anesthetics have previously been shown to reduce membrane dipole potential, − to the best of our knowledge, our results constitute the first experimental report of reduction in membrane dipole potential by a local anesthetic.…”

Anesthetic Mechanisms: Synergistic Interactions With Lipid Rafts and Voltage-Gated Sodium Channels

“…16 NA V CHANNELS AND LIPID RAFTS AS ANESTHETIC TARGETS Anesthetics enter cells through the membrane due to their lipid solubility and alter Na V function through different mechanisms. These mechanisms can include changes in lipid membrane properties such as variations in fluidity, permeability, or dipole potential, 121,124,125 affinities for different functional states of ion channels, 126 pore blockage, 127 binding or altering the selectivity filter of ion channels, 82 and modification of the inactivation state (Table ). 128 General anesthetics have low affinity and high exchange rates 82 which gives them nonspecific membrane-mediated action mechanisms.…”

“…Selectivity filter near DEKA motif, voltage-sensing linker (S4-S5) on DI, DIII, and DIV that may alter affinities for different functional states of the ion channel, fenestrations within the pore (particularly DIV), causing blockage using a charged residue 81,126 ; Extracellular site near selectivity filter in DIV (activation gate) 79,134 Increases diameter, area, and number of lipid rafts, increases PLD2 activity, altering membrane ion permeability, PLD2 translocates away from lipid rafts, enhancing PIP 2 regulation 25,62 ; Increases lipid lateral mobility and reduces mechanical stiffness of the plasma membrane 135 ; reduces sterolphospholipid association in L o domains 120 ; reduces membrane dipole potential 125…”

“…One of the major influences on lipid rafts comes from reducing sterol-phospholipid associations in L o domains 120,149 which affect lipid lateral mobility and reduces mechanical stiffness of the membrane, 135 and alters the membrane dipole potential. 125 Pavel et al 25 showed that volatile anesthetics increase the area and number of lipid rafts on cellular membranes. Regardless of the mechanism, alteration of the lipid membrane structure results in an increase in phospholipase DII (PLD2) activity and translocation, changes in membrane ion permeability, and enhanced PIP 2 regulation (Figure 4C).…”

Membrane Dipole Potential: An Emerging Approach to Explore Membrane Organization and Function

“…Table shows a comprehensive list of membrane proteins (and peptides) whose functions are known to be affected by a change in membrane dipole potential. In addition, dipole potential is sensitive to interaction of proteins with membrane. ,, Interestingly, the action of anesthetics has been shown to be via modulation of membrane dipole potential. ,− It has also been suggested that local dipole potential could play an important role in the function of proteins localized to specialized membrane microdomains, where the dipole potential is different from the bulk membrane due to the enrichment of cholesterol in these domains. , …”