Lipids anesthetic perturbations

Membrane conformational changes are observed on exposure to anesthetics, further supporting the importance of physical interactions that lead to perturbation of membrane macromolecules. For example, exposure of membranes to clinically relevant concentrations of anesthetics causes membranes to expand beyond a critical volume (critical volume hypothesis) associated with normal cellular function. Additionally, membrane structure becomes disorganized, so that the insertion of anesthetic molecules into the lipid membrane causes an increase in the mobility of the fatty acid chains in the phospholipid bilayer (membrane fluidization theory) or prevent the interconversion of membrane lipids from a gel to a liquid form, a process that is assumed necessary for normal neuronal function (lateral phase separation hypothesis). 

FIGURE 11-2 Schematic illustration of two possible ways general anesthetics may act on the nerve membrane. In the general perturbation theory, anesthetic molecules lodge in the lipid bilayer and inhibit sodium channel function by disrupting membrane structure. In the specific receptor theory, anesthetics inhibit the opening of the sodium channel by binding directly to the channel protein. 

Hence, it is believed that general anesthetics exert most, if not all, of their effects by binding to one or more neuronal receptors in the CNS. This idea is a departure from the general perturbation theory described earlier that is, that the inhaled anesthetics affected the lipid bilayer rather than a specific protein. Continued research will continue to clarify the mechanism of these drugs, and future studies may lead to more agents that produce selective anesthetic effects by acting at specific receptor sites in the brain and spinal cord. 

This question of direct interaction with nerve proteins or indirect interaction via membrane perturbation has also been tackled by ESR spectroscopy. Two types of labeling have been used fatty acids for lipid labeling and maleimide for frog nerve proteins. The anesthetics used were halothane as an example of a general anesthetic and procaine, lidocaine, and tetracaine as examples of local anesthetics. The latter interact primarily with head groups but can also merge into the hydrophobic hydrocarbon... 

Interaction of small molecules and ions with lipid bilayers is of importance from the point of view of membrane transport and other processes such as aaion of drugs and anesthetics on membranes. This includes a number of antibiotics and fatty acids also. The effect of these perturbations on the lipid bilayer in terms of differences in the structure and dynamics of the lipids close to the perturbative group versus the bulk lipids is also interesting and may... 

Like general anesthetics, ethanol appears to act by changing the fluidity of membrane lipids, leading to a perturbed function of the membrane proteins. During development of tolerance to ethanol, the membrane phospholipids acquire more saturated fatty acids, which seems to counteract the effects of ethanol on membrane function. 

Jelinek and co-workers demonstrated that the changes in fluorescence of PDA can be used to detect the interactions of drug molecules with the membranes of live cells. Diacetylene patches containing 10,12-tricosadiynoic acid were transferred from diacetylene vesicles to the membranes of leukemia cells and were polymerized with UV radiation. This fusion efficiency was found to depend on the lipid composition of the liposomes and the presence of cholesterol on the plasma membrane. The interactions of these cells with lidocaine (a local anesthetic), polymixin-B (an antibiotic), and oleic acid were studied by confocal fluorescence microscopy. The PDA patch on the live cells showed bright red fluorescence when the cell membranes were perturbed. The blue to red color change in the presence of oleic acid was apparent when the cells were sedimented by centrifugation. 

Anesthetics appear to abolish the short-range immobilization induced by proteins on lipids (tentatively ascribed to boundary lipids) in other words, there is a labilization of lipid proteins interactions induced by the membrane perturbation. This appears to us as an indirect proof in favor of the existence of boundary lipids. The disordering effect in membranes is induced at low anesthetic concentrations, compatible with those known to cause general anesthesia. 

The a-helix decrease induced by delipidation or perturbation of lipid-protein interactions by anesthetics has a theoretical explanation in the fact that an increased accessibility of water to peptide bonds induces a competition of H20-peptide hydrogen bonds with peptide-peptide hydrogen bonds that are required to stabilize secondary structure such as a-helix. 

Following Overton s early observation of the direct relationship between the efficacy of an alcohol and oil/water partition coefficient of that alcohol, most research concerning the mechanism of action of ethanol and similar anesthetics has focused on the interior of neuronal membranes and model membrane systems. The lipid perturbation hypothesis simply states that the effects of alcohols result from changes in the fluidity of the interior of the membrane. The observed changes in membrane order, however, are usually small or occur at nonphysiological concentrations of alcohol. ... 

If perturbation of the membrane interior is indeed the mechanism of anesthetic action, then the differences in alcohol sensitivity observed in test animals could be explained by differences in the animals membrane-lipid composition. In the last decade, mice have been genetically bred solely on the basis of their ethanol sensitivity. Two genetically different strains of mice, the long sleep mice (LS, ethanol sensitive mice) and the short sleep mice (SS, ethanol resistant mice), now exist. 

---