Mechanisms revealed through general anesthetic photolabeling
Brian P. Weiser, Kellie A. Woll, William P. Dailey, Roderic G. Eckenhoff,
University of Pennsylvania
Current Anesthiology Reports, 1 March 2014, 4(1) pp. 57-66
Summary and review of the above paper
General anaesthetic photolabels are used to find the molecular binding sites of anaesthetics, such as GABA receptors, protein kinase and tubulin. Mechanisms of anaesthesia.
Involvement of anaesthetics with voltage-dependent channels for negative ions and the mitochondria has been demonstrated by photolabelling. At clinical concentrations anaesthetics can effect the functioning of proteins. Photolabels can attach to residues or individual molecules lining protein pockets, and thus indicate the presence of a dynamic ligand in a pocket.
van der Waals
General anaesthetics are thought to interact in these protein pockets by means of hydrophobic or van der Waals forces. Photolabels are capable of providing evidence for high-energy interactions such as intermolecular hydrogen bonds. In the case of the anaesthetic, halothane, up to 15% of neuronal proteins are seen to be photolabeled by that anaesthetic, and this is also the proportion of proteins that contain cavities large enough to bind halothane. It appears that binding in membrane proteins can allow some binding of lipids at the protein/membrane interface.
Photolabeling has particularly identified some components of the mitochondrial respiratory complex and mitochondrial enzymes as binding partners of halothane, and general anaesthetics have been demonstrated to alter mitochondrial respiration. Halothane can be localized to mitochondria, but elsewhere anaesthetics bind to neural mechanisms that do not involve energy. Ion channels such as GABA ion channels have also been shown to be modulated by anaesthetics. GABA inhibitory neurons are essential for the maintenance of gamma synchronies. Anaesthetics as a group have multiple targets in the brain, with different anaesthetics having different affinities.
Tubulin is the primary component of microtubules. Alpha and beta tubulins are found in every type of neuron, and have been suggested as a target for general anaesthetics. Anaesthetic agents, including halothane, have been demonstrated to bind in such a way as to destabilize microtubules, but microtubules do not seem to respond to every anaesthetic in this way.