Remigijus Lape (Neuroscience, Physiology and Pharmacology, University College London , UK)
Abstract:Ligand gated ion channels are multimeric proteins composed of a couple of thousand amino acids. Protein molecules are in continuous structural fluctuation covering timescales that range from picoseconds to milliseconds. The timescale depends on the size of the structural elements involved in the motion. This ranges from single atoms, to the side chains of single amino acids, to several amino acids moving in a coordinated pattern. Larger scale conformational changes overcome higher energy barriers and give rise to few stable conformational states. Advances in high resolution recording of single channel activity allow us routinely to collect observations that contain a lot of information about conformational states with lifetimes as short as few microseconds. This led us to explore more and more detailed activation mechanisms of ligand gated receptors. In favourable cases we can estimate 18 free rate constants, far more than can be estimated by macroscopic methods. These detailed mechanisms are likely to be a more realistic description of the energy landscape of channel proteins than any previously available for these or other proteins. On the other hand the complexity of these mechanisms challenges our mathematical and computational techniques. I will overview current ideas about activation mechanisms in the nicotinic receptor family. Then I will discuss the most common problems in our work such as the choice of mechanisms and our ability to distinguish between alternative models and how to estimate a large number of free parameters.