College of Psychology: Faculty Proceedings, Presentations, Speeches and Lectures

Title

A Unitary Mechanism of Anesthesia?: Altering Collective Oscillations in Microtubules

Event Location / Date(s)

San Diego , California

Document Type

Pre-Conference Presentation

Presentation Date

6-6-2017

Conference Name / Publication Title

The Science of Consciousness 2017 Preconference Workshop: Quantum Brain Biology

Description

General anesthetics (GAs) remain one of the greatest serendipitous pharmacological discoveries known, however despite over a century of research the unitary mechanism by which they act to cause reversible loss of consciousness and memory remains a mystery. While the primary sites of anesthetic action have generally been accepted as membrane bound receptors, anesthetic actions at these sites has been shown to be varied and inconsistent, leading to a fruitless mechanistic description in terms of a unitary action of anesthesia. However, an often-overlooked site of action is the microtubule cytoskeleton. Proteomic and genomic evidence for functional anesthetic effects has pointed toward cytoskeletal microtubules inside neurons as a common, likely site of anesthetic action. As post-translational modifications of microtubules (i.e. phosrphoyrlation, detyrosination, glutamylation etc.) can generate a code that participates in memory formation, disruption of microtubules by anesthetics can lead to memory loss and even unconsciousness. Yet, the mystery of anesthesia is not simply determining the site of action. Rather the mystery stems from the puzzling structure-activity relationship of GAs, as effective agents can span a 35-fold range in molecular volume from a single atom (xenon) to 56-atom steroids, with numerous structures and configurations in between. What is known is that GAs are lipid-soluble and highly polarizable, and that their potency, regardless of structure, is approximately proportional to lipid solubility in a relationship known as the Meyer-Overton rule. This rule holds for GA activity in many species from paramecia to humans - and even plants. As anesthetic agents are inherently un-reactive, and work primarily via relatively weak dispersion forces, they alter induced van der Waals dispersion forces on structural collective modes in proteins. Here we discuss results of the effect of anesthetic, non-anesthetic, and convulsant molecules on dispersion forces in the microtubule constituent protein tubulin. As this mechanism has direct bearing on the link between anesthetic induced amnesia and unconsciousness, as well as its effect on neurodegenerative disease with compromised cytoskeletons, it has the potential to provide new insights on the site and mechanism of anesthetic action, and may also lead to the design and development of novel anesthetics free of potentially harmful side effects.

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