Structure of the GABA/A receptor

Published on April 2, 2014 Updated on April 6, 2014   44 min

Other Talks in the Series: Synapses, Neurotransmitters and Receptor Channels

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Today's presentation is on the structure of the GABAA receptor. For the central nervous system to function it has to have a degree of excitation, but that excitation can't be unstructured. And one of the most important ways to control this is by neurotransmitter GABA activating GABAA receptors to cause inhibition in the nervous system. Before we look at the structure of the receptor, I'd just like to take you through some elementary, basic introductory features of GABAA receptors and GABA itself.
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When you look at the central nervous system, GABA and GABAA receptors are spread quite ubiquitously right across the entire area of the brain and spinal cord. This is because they are involved in two very important physiological control mechanisms that are called synaptic inhibition and tonic inhibition. Synaptic inhibition involves the pulsatile release of relatively high concentrations of GABA at inhibitory synapses, whereas tonic inhibition is really the assistant level of low concentrations of GABA activating GABA receptors which lie outside the synapse, the so called extra-synaptic domain. Both of these aspects are important for controlling the spiking, action potential firing of individual nerve cells. There's another factor that's important for GABAA receptors and that's in development, during early on in immature neurons where by GABA can cause the outgrowth of neurites and the development of neurons. So there are many important physiological features that are associated with GABAA receptors and GABA. Now when there's dysfunction, this can involve a number of different diseases in the GABA system. Some diseases can be directly attributed to GABAA receptor dysfunction, such as anxiety and epilepsy. And other diseases and conditions are less direct, and this could be depression, Down's Syndrome, schizophrenia for example, Alzheimer's disease, and pain. But nevertheless, this slide shows you that not just physiologically, but pathologically, GABA has important roles to play in the nervous system. Now because of this, GABA receptors have become natural targets for drugs. Some are listed here on the right hand side. Barbiturates, Benzodiazepines, general anesthetics, and there are endogenous regulators of GABA receptors called neurosteroids. And it's no surprise then to find that a number of drugs are through to the market and are involved in the treatment of a variety of diseases. You'll notice that these are dominated by epilepsy. But there's also conditions whereby GABAergic drugs could be used for the treatment of pain, and also more recently for Alzheimer's disease. So what does the natural GABA receptor look like? This we can see in the next slide.