Surgery would be inconceivable without general anesthesia, so it may come as a surprise that despite its 175-year history of medical use, doctors and scientists have been unable to explain how anesthetics temporarily render patients unconscious.

A new study in the Proceedings of the National Academies of Sciences (PNAS) solves this longstanding medical mystery. Using modern nanoscale microscopic techniques, plus clever experiments in living cells and fruit flies, the scientists show how clusters of lipids in the cell membrane serve as a missing go-between in a two-part mechanism. Temporary exposure to anesthesia causes the lipid clusters to move from an ordered state, to a disordered one, and then back again, leading to a multitude of subsequent effects that ultimately cause changes in consciousness.

The discovery settles a century-old scientific debate, one that still simmers today: Do anesthetics act directly on cell-membrane gates called ion channels, or do they somehow act on the membrane to signal cell changes in a new and unexpected way? It has taken nearly five years of experiments, calls, debates and challenges to arrive at the conclusion that it's a two-step process that begins in the membrane, the authors say. The anesthetics perturb ordered lipid clusters within the cell membrane known as "lipid rafts" to initiate the signal.

Using Nobel Prize-winning microscopic technology, specifically a microscope called dSTORM, short for "direct stochastical optical reconstruction microscopy," a post-doctoral researcher bathed cells in chloroform and watched something like the opening break shot of a game of billiards. Exposing the cells to chloroform strongly increased the diameter and area of cell membrane lipid clusters called GM1, the author explains.

What the author was looking at was a shift in the GM1 cluster's organization, a shift from a tightly packed ball to a disrupted mess. As it grew disordered, GM1 spilled its contents, among them, an enzyme called phospholipase D2 (PLD2).

Tagging PLD2 with a fluorescent chemical, the authors were able to watch via the dSTORM microscope as PLD2 moved like a billiard ball away from its GM1 home and over to a different, less-preferred lipid cluster called PIP2. This activated key molecules within PIP2 clusters, among them, TREK1 potassium ion channels and their lipid activator, phosphatidic acid (PA). The activation of TREK1 basically freezes neurons' ability to fire, and thus leads to loss of consciousness, the author says.

"The TREK1 potassium channels release potassium, and that hyper-polarizes the nerve--it makes it more difficult to fire--and just shuts it down," the author says.

The authors validated the findings in a living animal model. The common fruit fly, drosophila melanogaster, provided that data. Deleting PLD expression in the flies rendered them resistant to the effects of sedation. In fact, they required double the exposure to the anesthetic to demonstrate the same response.

"All flies eventually lost consciousness, suggesting PLD helps set a threshold, but is not the only pathway controlling anesthetic sensitivity," they write.

The authors say the discoveries raise a host of tantalizing new possibilities that may explain other mysteries of the brain, including the molecular events that lead us to fall asleep.

https://www.pnas.org/content/early/2020/05/27/2004259117

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