Membrane Protein Hypothesis of General Anaesthetic Action
In the early 1980s, Franks and Lieb demonstrated that the Meyer-Overton correlation can be reproduced using a soluble protein. They found that two classes of proteins are inactivated by clinical doses of anaesthetic in the total absence of lipid. These are luciferases, which are used by bioluminescent animals and bacteria to produce light, and cytochrome P450, which is a group of heme proteins that hydroxylate a diverse group of compounds, including fatty acids, steroids, and xenobiotics such as phenobarbital. Remarkably, inhibition of these proteins by general anaesthetics was directly correlated with their anaesthetic potencies. Luciferase inhibition also exhibits a long-chain alcohol cutoff, which is related to the size of the anaesthetic-binding pocket.
These observations were important because they demonstrated that general anaesthetics may also interact with hydrophobic protein sites of certain proteins, rather than affect membrane proteins indirectly through nonspecific interactions with lipid bilayer as mediator. It was shown that anaesthetics alter the functions of many cytoplasmic signalling proteins, including protein kinase C, however, the proteins considered the most likely molecular targets of anaesthetics are ion channels. According to this theory general anaesthetics are much more selective than in the frame of lipid hypothesis and they bind directly only to small number of targets in CNS mostly ligand(neurotransmitter)-gated ion channels in synapse and G-protein coupled receptors altering their ion flux. Particularly Cys-loop receptorsare plausible targets for general anaesthetics that bind at the interface between the subunits. The Cys-loop receptor superfamily includes inhibitory receptors (GABA A, GABA C, glycine receptors) and excitatory receptors (acetylcholine receptor and 5-HT3 serotonin receptor). General anaesthetics can inhibit the channel functions of excitatory receptors or potentiate functions of inhibitory receptors, respectively. Although protein targets for anaesthetics have been partly identified the exact nature of general anaesthetic-protein interactions still remains a mystery.
It was initially hypothesized that general anaesthetic binds to its target ion channel by a key-lock mechanism and changes its structure dramatically from open to closed conformation or vice versa. However, there is lots of evidence accumulated against direct key-lock interaction of membrane proteins with general anaesthetics
Various studies have shown that low affinity drugs including inhaled general anaesthetics do not usually interact with their target proteins via specific lock-and-key binding mechanism because they do not change molecular structures of transmembrane receptors, ion channels and globular proteins. Based on these experimental facts and some computer simulations modern version of protein hypothesis was proposed. Proteins of four-α-helix bundle structural motif served as models of monomer of pentameric Cys-loop receptor because binding pockets of inhaled anaesthetics are believed to be within transmembrane four-α-helix bundles of Cys-loop receptors. Inhaled general anaesthetic does not change structure of membrane channel but changes its dynamics especially dynamics in the flexible loops that connect α-helices in a bundle and are exposed to the membrane-water interface. It is a well known fact that dynamics of protein in microsecond-millisecond timescale is often coupled with functions of the protein. Thus it was logical to propose that since inhaled general anaesthetics do not change protein structure they may exert their effect on proteins by modulating protein dynamics in a slow microsecond-millisecond timescale and/or by disrupting the modes of motion essential for function of this protein. Normal interactions between residues in protein regions (loops) at the water-lipid interface that play critical roles in protein functions and agonist binding may be disrupted by general anaesthetic. Interactions within the same loop or between different loops may be disrupted by anaesthetics and ultimately functions of Cys-loop receptors may be altered.
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