Membrane nanodomains homeostasis during propofol anesthesia as function of dosage and temperature.

Abstract

Some anesthetics bind and potentiate γ-aminobutyric-acid-type receptors, but no universal mechanism for general anesthesia is known. Furthermore, often encountered complications such as anesthesia induced amnesia are not understood. General anesthetics are hydrophobic molecules easily dissolving into lipid bilayers. Recently, it was shown that general anesthetics perturb phase separation in vesicles extracted from fixed cells. Unclear is whether under physiological conditions general anesthetics induce perturbation of the lipid bilayer, and whether this contributes to the transient loss of consciousness or anesthesia side effects. Here we show that propofol perturbs lipid nanodomains in the outer and inner leaflet of the plasma membrane in intact cells, affecting membrane nanodomains in a concentration dependent manner: 1 μM to 5 μM propofol destabilize nanodomains; however, propofol concentrations higher than 5 μM stabilize nanodomains with time. Stabilization occurs only at physiological temperature and in intact cells. This process requires ARP2/3 mediated actin nucleation and Myosin II activity. The rate of nanodomain stabilization is potentiated by GABAA receptor activity. Our results show that active nanodomain homeostasis counteracts the initial disruption causing large changes in cortical actin. SIGNIFICANCE STATEMENT: General anesthesia is a routine medical procedure with few complications, yet a small number of patients experience side-effects that persist for weeks and months. Very young children are at risk for effects on brain development. Elderly patients often exhibit subsequent amnesia. Here, we show that the general anesthetic propofol perturbs the ultrastructure of the lipid bilayer of the cell membrane in intact cells. Initially propofol destabilized lipid nanodomains. However, with increasing incubation time and propofol concentration, the effect is reversed and nanodomains are further stabilized. We show that this stabilization is caused by the activation of the actin cortex under the membrane. These perturbations of membrane bilayer and cortical actin may explain how propofol affects neuronal plasticity at synapses.

• Authors: Weixiang Jin, Michael Zucker, Arnd Pralle
• Journal: Biochimica et biophysica acta. Biomembranes (Biochim Biophys Acta Biomembr) Vol. 1863 Issue 2 Pg. 183511 (02 01 2021) ISSN: 1879-2642 [Electronic] Netherlands
• PMID: 33245892 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Anesthetics, Intravenous
• Propofol

Topics

• Anesthesia
• Anesthetics, Intravenous (pharmacology)
• Animals
• Cell Line
• Dose-Response Relationship, Drug
• Homeostasis (drug effects)
• Hot Temperature
• Male
• Membrane Microdomains (metabolism)
• Potoroidae
• Propofol (pharmacology)