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Single Ion Channels: Receptor and Synaptic Mechanisms

Professor David Colquhoun, FRS

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Professor D Colquhoun, FRS held the established (A.J. Clark) chair of Pharmacology at UCL, and was the Hon. Director of the Wellcome Laboratory for Molecular Pharmacology. In October 2004, he became a Research Fellow. Like many previous holders of the chair (in particular, A.J. Clark, J.H. Gaddum, H.O. Schild and J.W. Black) his interests are in quantitative analysis of receptor mechanisms.

He graduated from Leeds with a BSc and then went to Edinburgh to work for a PhD. After doing research at University College from 1964-69 on immunological problems and completing a book on statistics, he went to Yale University to work on nerve conduction. After returning from the USA he eventually returned to the Pharmacology Department at UCL in 1979, and has worked on single ion channel mechanisms since then.  [interview] [bio]

In 2004, he was made an Honorary Fellow of University College London.

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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).

Analysis and theory

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).

We run a graduate school course each June or July, in which the necessary mathematical background for the understanding of these methods is taught. Photographs for the 2003 and 2004 schools here.


Analysis programs

We have developed, in the course of our work, a number of programs for single channel analysis, for curve fitting and for theoretical calculations. They have a lot of features that are not available in any commercial program, and they are free (for academic users).

Click HERE for descriptions of DC Analysis programs


Opening and shutting of a nicotinic ACh channel

(Modified, with permission, from Unwin, N. (2003) FEBS Letters, 555, 91-95)

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This page last modified 8 March, 2012 by David Colquhoun

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