Neurotransmitters mediate the communication between nerve cells in the brain. Once released at the synapse - the contact site between nerve cells - neurotransmitters propagate signals to neighbouring neurons. To allow fast and accurate signal processing in the brain neurotransmitters must be removed rapidly from the site of action. This resets the signal transduction process so that the next nerve impuls can be transmitted. Removal of neurotransmitters is accomplished by transporters, which capt ....Neurotransmitters mediate the communication between nerve cells in the brain. Once released at the synapse - the contact site between nerve cells - neurotransmitters propagate signals to neighbouring neurons. To allow fast and accurate signal processing in the brain neurotransmitters must be removed rapidly from the site of action. This resets the signal transduction process so that the next nerve impuls can be transmitted. Removal of neurotransmitters is accomplished by transporters, which capture the neurotransmitters and bring them back into neurons and astrocytes, the two major cell types in the brain. Malfunction of these transporters can cause mood disorders, Parkinsons's disease and may play a role in the onset of amyotrophic lateral sclerosis and other neurodegenerative disorders. In this project we try to identify novel neurotransmitters transporters, which are likely to play an important role in neurotransmission. Previously, these transporters were assigned as orphan transporters to indicate our lack of understanding. However, recent results from our laboratory now allows to identify the function of these transporters. Elucidation of the physiological role of these transporter will provide the basis to study their function and role in health and disease.Read moreRead less
Structural Determinants Underlying High Conductance GABA-A Channels
Funder
National Health and Medical Research Council
Funding Amount
$364,080.00
Summary
Large proteins called GABA-A receptors distributed widely throughout the brain are responsible for inhibition in most neurons. 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, but these valuable drugs still have unwanted side effects. For example, some of them affect cardiac and respiratory function. There is still a need for new, more effec ....Large proteins called GABA-A receptors distributed widely throughout the brain are responsible for inhibition in most neurons. 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, but these valuable drugs still have unwanted side effects. For example, some of them 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. The leading general anaesthetics, anxiolytic and anti-epileptic drugs currently used, 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 by serendipity. 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. In this project we plan to examine what the functional consequences are and how GABA-A receptors colocalise in the membrane, akin to their physical state in the brain. We will examine the effects of drugs on receptors colocalised in the membrane. We have preliminary evidence suggesting that when GABA-A receptors are close to each other they open together so that their inhibitory response is maximised. Drugs are also able to make GABA-A receptors open in concert. The concept that receptors in the membrane talk to each other has been shown to occur for receptors from different classes but we now have evidence that the same type of receptors i.e. GABA-A receptors, are able to talk to each other.Read moreRead less