Video transcript: Scientists determine structure of brain receptor implicated in epilepsy and PMT

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March 2008

Dr Mike Edwardson
"So we’ve been working on the stretch of a receptor for a neurotransmitter called GABAA, gamma-aminobutyric acid. This transmitter is the major inhibitory transmitter in the brain. So what it does is it binds to the receptor and that will then reduce the firing rate of neurons. The receptor itself is known to be made from five sub-units, so it’s a pentamer, and there are various different types of sub-units from which the receptor can be made. And the one we’ve been interested in is one that contains a unit called the delta sub-unit. What’s interesting about this is that the receptor is not localised at synapses, which are the junctions between the neurons. The receptor is actually spread all over the surface of the neuron, and what it does is it seems to damp down neuronal activity generally."

"So the receptor, although it’s not a major type of GABA receptor, is very widely distributed in the brain. It seems to have this general role of what’s called tonic inhibition, this damping-down neuronal activity. The technique we use to look at the structure of the receptor is a technique called atomic force microscopy, and this works in a very different way from a normal light microscope. It scans a very sharp tip over the surface of the sample. The sample is stuck to a mica disk, which is a very flat surface, and as the tip is moving back and to over the surface, if it encounters a particle it is deflected and the deflections of the tip are picked up and used to create an image of the sample that we’re looking at."

"The image, which you can see on the screen, is being built up line by line and you may be able to see that there are white blobs on the screen. These are the individual receptors that we’re imaging. Each of these receptors is about 10 or 20 nanometers in diameter, so it’s very tiny and we’re able to see things at a higher resolution than any light microscope for example. It’s almost approaching the resolution that you get with an electron microscope."

"In this way, by looking at the geometry of the complexes, we can figure out the arrangements of the sub-units around the receptor. So we now know what the arrangement is and this is of interest because we know that a lot of drugs that interact with these GABA receptors are binding at the interfaces, the junctions, between the various sub-units. We have now defined what these drug-binding sites look like because we know now what all the interfaces are around the receptor. So it’s possible now for us to think about modelling the structure of the receptor, and particularly the potential drug-binding sites at the interfaces, between the sub-units. So in the long-term it’s possible that this new information will allow us to think about a rational design of new drugs that will act specifically on this particular type of receptor, the delta-containing receptor. It’s been implicated in a number of conditions. The first condition is pre-menstrual tension. It’s known in rats that the levels of the receptor change during the ovarian cycle. Now in humans before menstruation there is a sharp fall in the levels of progesterone, which is acting upon these receptors, and it’s been shown in rats that the numbers of the delta-containing receptors increase during the equivalent period in the ovarian cycle. So, as a consequence of this, the excitability of the rats increases at this time. Now it’s a long jump between rats and humans, but if we can make that jump, it’s possible that there’s a similar thing going on in humans, where, just before menstruation, the levels of these receptors will rise, and this might contribute to some of the symptoms of pre-menstrual tension."

"Another condition where the delta sub-unit has been implicated is epilepsy. In epilepsy what’s happening is the neuronal activity is uncontrolled so there’s an excessive amount of activity, and in various animal models of this condition, the levels of the delta sub-unit-containing receptors fall, which may account for this over-excitability. Also in some human forms of epilepsy, variations in the sequence of the delta sub-unit seem to be occurring. So it’s possible that in epilepsy as well, there is an involvement of the delta-containing receptor."

"Finally there is some evidence that this particular type of receptor is extremely sensitive to alcohol. Most of the GABA receptors are sensitive to alcohol, but the delta-containing ones are especially sensitive. And indeed, sensitive to levels of alcohol that are present in the brain, even during social drinking. So it’s possible that the delta-containing receptor is mediating some of the effects of even quite moderate amounts of alcohol."

"The control of neuronal function depends upon a balance between what are called excitatory and inhibitory inputs, so each neuron is working by firing what are called action potentials. So the activity of an individual neuron depends upon inputs it’s getting from its neighbours. So some of the neurons are releasing transmitters that are excitatory, and they will act on the receptors and increase the firing rate of the target neuron. Other neurons are releasing inhibitory messengers, inhibitory transmitters, for example GABA, which will then bind to the receptor and reduce the firing rate and reduce the activity of the target neuron. So normal brain function depends on a controlled balance between these excitatory and inhibitory effects, and if we go one way or the other, that will produce abnormal brain function. For example, in epilepsy excitation predominates and therefore all of the neurons are firing too rapidly. Then you see the effects of epilepsy, which are things like convulsions. So we’ve got to maintain this balance between excitatory and inhibitory input into each neuron. And the GABA is the inhibitory messenger."