AddressG50 Med Sci
Neuroscience, Physiology & Pharmacology
Medical Sciences Building, G50, UCL
Emeritus Professor of Pharmacology
Div of Biosciences
Faculty of Life Sciences
Neuro, Physiology & Pharmacology
Div of Biosciences
Transmission of an impulse from one nerve cell to another, or to a muscle cell, occurs by the release of a chemical substance, such as acetylcholine or glutamate, which combines with specific protein molecules- receptors- in the membrane of the downstream cell.
These receptors form molecular pores which span the cell membrane, and the combination of the transmitter with them causes the pore to open, which allows the passage of sodium and other ions. The current caused by movement of these ions across the membrane then initiates an electrical impulse.
We are studying the receptors for glutamate, acetylcholine and glycine by a combination of biophysical and molecular biological approaches. We record the currents through individual receptor-channels which are in their natural environment, the membranes of nerve cells from the brain or ganglia. We also record from channels that have been made from cloned DNA and artificially inserted into a convenient cell membrane. The latter method has the advantage that (with luck) you know which molecule you are dealing with, and also that altered receptors can be made by mutating the amino acid sequence of the receptor proteins. These methods allow us to address a variety of questions.
A major question that concerns us is the exact molecular nature of the receptors that occur in living cells in various parts of the nervous system. At a more basic level we are interested in the nature of the molecular interactions that cause the channels to open and shut, and what it is that controls the speed of synaptic events. Once one knows the rates of individual steps in the ion channel reaction mechanism, the binding-gating problem is solved, the way is cleared for rational interpretation of the effects of mutations in the receptor protein, and the response to any arbitrary time course of synaptic concentration of transmitter can be calculated. We have taken this approach to analysis of natural disease-causing mutations in human muscle nicotinic acetylcholine receptors, and in human glycine receptors (the latter being in collaboration with Sivilotti's lab).
We have also been closely involved in developing new methods for the analysis of single channel recordings which, because they originate from single molecules, are random in nature. And, in collaboration with Professor A.G. Hawkes (who does all the difficult stuff), we have developed much of the underlying stochastic theory which is necessary for the interpretation of these recordings. This theory allows us to interpret single channel recordings in which short events are undetected, and most recently has been extended to deal with non-stationary channels, such as those observed after a brief pulse of agonist is applied. This theory has proved essential for the interpretation of our experimental observations. For example, we have been interested in questions such as 'what does an individual activation of an ion channel look like, and how is it related to synaptic currents?', 'how can we understand the effect of mutating an amino acid in the receptor?', and 'how can we tell whether a particular amino acid forms part of the binding site?'. One outcome of the theory has been the development of an optimum method (the HJCFIT program) for estimation of rate constants in a mechanism, with exact correction for missed events).
Doctor of Philosophy
|University of Edinburgh|
Bachelor of Science (Honours)
|University of Leeds|
There is a synopsis in my Wikipedia entry. http://en.wikipedia.org/wiki/David_Colquhoun