Mechanism of anaesthetic activation, combination and antagonism
type: CreativeWork
description: The type A γ-aminobutyric acid receptors (GABAAR) – pentameric ligand gated ion channels (pLGICs) – are the main mediators of fast inhibitory neurotransmission in the human brain. Malfunctions in these receptors are a common cause for neurological disorders such as anxiety, epilepsy, schizophrenia and insomnia. Fortunately, due to numerous binding sites and decades of dedicated research, a large library of GABAAR targeting drugs is available to treat such conditions. The most prominent group of ligands targeting GABAA receptors are general anaesthetics. The effects of anaesthetics on the human body such as immobility, analgesia, amnesia and muscle relaxation are exploited during surgery and are indispensable in modern medicine to allow invasive procedures. Although the binding sites of several anaesthetics have been identified through structural and functional experiments, the underlying mechanism of such drugs remains unclear. In the first chapter of this thesis, I will use a series of high resolution cryo-EM structures to elucidate the mechanism of general anaesthetics on the human α1β3γ2L GABAA receptor. Etomidate and propofol were chosen as examples due to their clinical importance. I will further compare the ligand’s impact on the receptor with the physiological GABA-triggered activation mechanism. I will address concerns regarding different receptor reconstitution systems such as membrane-scaffold protein (MSP)-, saposin-, and SMALP nanodiscs. Antibody fragments have been used in the past to support particle alignment and distribution in cryo-EM specimen. On the example of several cryo-EM structures, I will discuss the impact and necessity of such fiducials. Anaesthetics are thought to target the inter-subunit clefts of several pLGICs in the TMD. In the second chapter of this work, I will present several structures of the α1β3γ2L GABAA receptor with ligands occupying unexpected and previously missed binding sites including the historically labelled ‘orphan’ in…
abstract: The type A γ-aminobutyric acid receptors (GABAAR) – pentameric ligand gated ion channels (pLGICs) – are the main mediators of fast inhibitory neurotransmission in the human brain. Malfunctions in these receptors are a common cause for neurological disorders such as anxiety, epilepsy, schizophrenia and insomnia. Fortunately, due to numerous binding sites and decades of dedicated research, a large library of GABAAR targeting drugs is available to treat such conditions. The most prominent group of ligands targeting GABAA receptors are general anaesthetics. The effects of anaesthetics on the human body such as immobility, analgesia, amnesia and muscle relaxation are exploited during surgery and are indispensable in modern medicine to allow invasive procedures. Although the binding sites of several anaesthetics have been identified through structural and functional experiments, the underlying mechanism of such drugs remains unclear. In the first chapter of this thesis, I will use a series of high resolution cryo-EM structures to elucidate the mechanism of general anaesthetics on the human α1β3γ2L GABAA receptor. Etomidate and propofol were chosen as examples due to their clinical importance. I will further compare the ligand’s impact on the receptor with the physiological GABA-triggered activation mechanism. I will address concerns regarding different receptor reconstitution systems such as membrane-scaffold protein (MSP)-, saposin-, and SMALP nanodiscs. Antibody fragments have been used in the past to support particle alignment and distribution in cryo-EM specimen. On the example of several cryo-EM structures, I will discuss the impact and necessity of such fiducials. Anaesthetics are thought to target the inter-subunit clefts of several pLGICs in the TMD. In the second chapter of this work, I will present several structures of the α1β3γ2L GABAA receptor with ligands occupying unexpected and previously missed binding sites including the historically labelled ‘orphan’ in…
author: Miehling, Jonas
language: eng
keywords: GABA receptor, GABAA, GABAAR, Anaesthetics, Etomidate, Antidote, Propofol, Barbiturate, Alphaxalone, structural biology, cryo EM, cryo electron microscopy, pharmacology
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2022-03-31
date modified: 2026-07-22T22:24:24Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.87926