Y. Bourne / P. Marchot’s team guest: Scott B. Hansen, The Scripps Research Institute & UF Scripps, Jupiter, Florida – “Molecular Basis of General Anesthesia”

Abstract

Anesthetics are a chemically diverse group of molecules that modulate neuronal excitability, forming the cornerstone of modern medicine. Understanding their molecular mechanisms is essential for unraveling the complexities of nerve excitability, mood regulation, consciousness, and psychiatric disorders. For over a century, the non-specific chemical nature of anesthetics led researchers to hypothesize that their site of action was the plasma membrane, although a definitive site remained elusive.

Our recent work has identified an anesthetic binding site within ordered lipid domains, commonly known as lipid rafts. We discovered that anesthetics compete with palmitate—a 16-carbon lipid that covalently attaches proteins to specific sites within the membrane. This competition results in the release of a complex of Twik-related potassium channels (TREK-1) from lipid rafts, altering the lipid environment and activating the channel.

In this talk, I will explore a similar mechanism in Cys-loop receptors, with a focus on gamma-aminobutyric acid (GABA) A receptors (GABA_AR). Our findings reveal that the endogenous agonist GABA causes GABA_ARs to dissociate from lipid rafts and relocate to clusters of phosphatidylinositol 4,5-bisphosphate (PIP2). We further demonstrate that inhaled anesthetics and propofol mimic GABA by releasing GABA_ARs from lipid rafts.

Finally, I will discuss how this process is regulated in neurons by astrocyte-derived cholesterol. We conclude that astrocytic cholesterol drives hyperexcitability in neurons, and anesthetics counteract the effects of cholesterol to induce anesthesia.