Effects of mutations in the conserved cysteine loop of the GABA-A receptor

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Inhibiting excitatory signals in the brain is the function of large proteins called GABA-A receptors. Many general anaesthetics, tranquillisers and anti-epileptic drugs act by modulating GABA-A receptors. Modern surgery would not be possible without rendering patients unconscious with general anaesthetics. However, these valuable drugs can still have unwanted side effects: for example, some of them can affect cardiac and respiratory function. There is still a need for new, more effective general anaesthetics. One in every 200 people in Europe and North America suffers from epilepsy and 3% of the population suffers from anxiety. Leading, currently used general anaesthetics, anxiolytic and anti-epileptic drugs act on GABA-A receptors in the brain. The potential annual market for these drugs has been estimated to be US $2.7 billion. The world market for anaesthetics in 1999 was US $1.6 billion. All were discovered serendipitously. If the molecular site and mode of action of these drugs were understood, it is possible that new, more selective drugs could be discovered. The information gained in this project about GABA-A receptors is expected to be useful in understanding how these receptors work and in developing a new generation of drugs acting on GABA-A receptors. Specific mutations in GABA-A receptors can have a profound influence on their function. Studying the effects of mutations is slowly giving us more information about the ion channel region and drug binding sites. Recently, mutations in GABA-A receptors have been found to be associated with some forms of epilepsy. In this project, we plan to examine the effects of mutations in highly conserved residues of a small region of subunits of the GABAA receptor because: (1) we (and others) have preliminary evidence that this loop forms a connection between the GABA binding site and the ion channel and (2) we think that this part of the receptor is vital for the effects of some drugs.