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Wake Me Up! Anaesthesia, a Membrane Mediated Loss of Sensation?

Membrane mediated effects of ketamine in lipid model membranes, as follows from by SAXS and molecular dynamics simulations, Imay affect the opening probability of ion channels of the central nervous system at clinically relevant concentrations by changing the internal pressure field of lipid membranes.
H. Jerabek et al., J. Am. Chem. Soc.132, 7990 (2010).

Figure 1. Lateral pressure profiles of POPC membranes at various concentrations (mol%) of the anaesthetic drug ketamine. The bar plot shows the distribution of ketamine.

Most probably everyone reading this article has already encountered several times in his life one of the most important, if not “the” most important drugs of human mankind: Anaesthetics. Without them modern surgery would just not be possible, and even simple medical interventions as those carried out by your dentist would become unbearable. Yet, despite their daily successful application for more than 160 years, we do not know how these drugs act on the molecular level. The quest for molecular targets boils down to two possibilities. Either anaesthetics directly act on ion channels of the central nervous system, or they change the biophysical properties of nerve membranes such that neurotransmission signals are affected. Arguments can be found in favour of one or the other target and the controversy on this issue is almost as old as the clinical use of anaesthetics.
We set out to study a mechanism that in a way integrates both views. Membrane proteins such as ion channels are under a constant field of lateral pressure, which is caused by the collective properties of the lipid membrane. When they open up and act as passive channels for the exchange of ions, they have to do this against the lateral pressure field, which costs some work. The idea is simple, yet very powerful. If an anaesthetic drug inserts into the membrane it will change its lateral pressure field, such that the work that the protein needs to perform for opening the channel is different. Thus, it couples via membrane properties mechanically to the opening probability of ion channels.
 
It is very difficult to determine the lateral pressure field experimentally. However, it is possible to measure its integral parameters, such as the membrane thickness, lateral area per lipid or bending rigidity. Because effects can be expected to be small, in particular at clinically relevant drug concentration, ultra-high structural resolution as provided by the SAXS beamline at Elettra is of need. Nerve membranes were mimicked by vesicles composed of the phospholipid palmitoyl oleoyl phosphatidylcholine (POPC) to which well defined amounts of ketamine was added. Diffraction patterns were analysed in terms of a full q-range model both in terms of the membrane thickness and area per lipid. Interestingly, neither of these parameters showed significant changes in the concentration range of 0 – 8 mol% ketamine. Therefore, we performed molecular dynamics (MD) simulations in order to trace the effects to molecular details. Moreover, MD simulations allow to derive lateral pressure fields in membranes. The MD simulations confirmed our experimental observations. However, at the same time we found significant changes to the pressure field (Fig. 1). In particular, the results demonstrated that ketamine locates preferentially close to the lipid/water interface and shifts the lateral pressure field toward the centre of the membrane. These results allowed us to calculate the consequent inhibition of ion channels applying simple protein models (Fig. 2). The half value (IC50), where 50% of the ion channels are inhibited was found to be either at 2 mol% or 18 mol%, respectively, depending on the protein geometry. It can be estimated that this corresponds to ketamine concentrations of 0.08 µM and 0.9 µM, respectively, in the blood. These values compare favourably with concentrations of ketamine in clinical applications. Results strongly encourage a further exploitation of membrane mediated effects of anaesthetics, which we think may lead to novel ways for designing membrane active anaesthetic drugs.
 

 

Figure 2. Effect of lateral pressure changes on the opening probability of ion channels. Either n-mers of tilted helices or bent helices were used as simple geometric models for the membrane proteins.
 

 

Retrieve article
Membrane-mediated effect on ion channels induced by the anesthetic drug ketamine;
H. Jerabek, G. Pabst, M. Rappolt, and T. Stockner; J. Am. Chem. Soc. 132, 7990 (2010).
10.1021/ja910843d
Last Updated on Monday, 10 February 2014 19:12