Mechanism Of Signal Transduction And Receptor Activation In Ligand Gated Ion Channel Receptors
Funder
National Health and Medical Research Council
Funding Amount
$456,000.00
Summary
This project seeks to provide fundamental new information about the means by which neurotransmitter receptors, which mediate fast synaptic neurotransmission, operate. It will use a range of molecular advances made by this and other laboratories to clarify how neurotransmitters enable their receptors to activate and signal. This fundamental information is of major medical significance as defective synaptic transmission, caused by mutations in ligand gated ion channel receptors, give rise to a num ....This project seeks to provide fundamental new information about the means by which neurotransmitter receptors, which mediate fast synaptic neurotransmission, operate. It will use a range of molecular advances made by this and other laboratories to clarify how neurotransmitters enable their receptors to activate and signal. This fundamental information is of major medical significance as defective synaptic transmission, caused by mutations in ligand gated ion channel receptors, give rise to a number of neurological and psychiatric disease states. The ligand gated receptors are also major targets for therapeutic drugs and the information gained in this study may also provide insights into new ways in which drugs could be used to enhance or inhibit synaptic signalling.Read moreRead less
Molecular Determinants Of Inhibitory Synaptic Function Studied Using Mutant And Transgenic Mice
Funder
National Health and Medical Research Council
Funding Amount
$496,500.00
Summary
Communication between nerve cells is the key to effective brain function and when disturbed, pathological states such as epilepsy, schizophrenia, fear and anxiety, spasticity and motor disorders ensue. This project is based on new data which suggests that the site of this communication, called the synapse, is a much more dynamic structure than previously thought. Based on our work to date, where we have demonstrated the recruitment of selected classes of neurotransmitter receptors into synapses, ....Communication between nerve cells is the key to effective brain function and when disturbed, pathological states such as epilepsy, schizophrenia, fear and anxiety, spasticity and motor disorders ensue. This project is based on new data which suggests that the site of this communication, called the synapse, is a much more dynamic structure than previously thought. Based on our work to date, where we have demonstrated the recruitment of selected classes of neurotransmitter receptors into synapses, our aim is to use a range of naturally occuring mice mutants, as well as transgenic mice to modulate the receptor levels and so to examine the role of synaptic function and synaptic dynamics. The outcomes of this project will provide fundamental new knnowledge aimed at understanding how communication in the nervous system works and may suggest ways in which modulation of this information flow could be used to treat disorders of brain function.Read moreRead less
Examining The Role Of ASIC Channels In Pain Through The Development Of Subtype-specific ASIC Channel Modulators.
Funder
National Health and Medical Research Council
Funding Amount
$617,256.00
Summary
Acid sensing ion channels (ASICs) sense changes in acidity in the body. They are found throughout the body and may underlie nerve damage in stroke and some types of pain. ASICs also have many as yet unknown functions. A lack of selective tools to study ASICs is a major barrier to a complete understanding of what they do. This proposal aims to modify three animal toxins which block these receptors to make useful tools to study their function, in particular their role in sensing pain.
Targeting Post-translational Modifications In TRPV Pain Channels
Funder
National Health and Medical Research Council
Funding Amount
$480,127.00
Summary
The same nerve receptor that binds the pungent component of chilli peppers (TRPV1) is an important part of our pain pathway. TRPV1 also responds to painful heat and acids. Chronic pain is an important unmet medical need and it uses the TRPV1 pathway. After activation by chilli, a feedback system in nerves inactivates TRPV1 and stops pain signalling. This feedback changes in chronic pain. This project aims to understand and exploit this feedback mechanism to find new approaches to pain therapy.
Identification Of Novel Therapeutic Binding Sites On Glycine Receptors By High Throughput Screening
Funder
National Health and Medical Research Council
Funding Amount
$542,017.00
Summary
Glycine receptors mediate inhibitory neurotransmission in the nervous system. They provide fresh therapeutic targets for chronic inflammatory pain and muscle spasticity. Here we identify 5 compounds that may be appropriate as leads for discovering novel therapies for these disorders. We will use automated high throughput screening methods to discover how these drugs interact with the receptor. This will narrow down the search for the next generation of analgesic and muscle relaxant drugs.
Developing Novel Selective Glycine Receptor Potentiators As A Means To Control Pain.
Funder
National Health and Medical Research Council
Funding Amount
$552,647.00
Summary
It has been estimated that >3M Australians suffer from pain at a cost to the economy of >$34B, with chronic pain (persisting beyond 1-6 mths) accounting for ~half this burden. There is an urgent and compelling social and economic case for the development of safer and more effective pain therapeutics. This project takes inspiration from a new class of Australian marine natural products that selectively regulate a key pain pathway, and will optimize and develop these as a new class of pain d ....It has been estimated that >3M Australians suffer from pain at a cost to the economy of >$34B, with chronic pain (persisting beyond 1-6 mths) accounting for ~half this burden. There is an urgent and compelling social and economic case for the development of safer and more effective pain therapeutics. This project takes inspiration from a new class of Australian marine natural products that selectively regulate a key pain pathway, and will optimize and develop these as a new class of pain drug.Read moreRead less
Therapeutic Potential Of Glycine Receptors In Pain Sensory Pathways
Funder
National Health and Medical Research Council
Funding Amount
$292,223.00
Summary
Inflammation caused by infection or injury leads to a heightened sensation of pain and can convert non-painful stimuli (e.g., touch) into painful stimuli. This effect is mediated by the production of prostaglandins both in peripheral tissues and in the spinal cord. Prostaglandins have recently been shown to decrease the magnitude of the inhibitory neurotransmission that normally occurs onto pain sensing neurons in the spinal cord. This has the effect of raising the excitability of these neurons, ....Inflammation caused by infection or injury leads to a heightened sensation of pain and can convert non-painful stimuli (e.g., touch) into painful stimuli. This effect is mediated by the production of prostaglandins both in peripheral tissues and in the spinal cord. Prostaglandins have recently been shown to decrease the magnitude of the inhibitory neurotransmission that normally occurs onto pain sensing neurons in the spinal cord. This has the effect of raising the excitability of these neurons, thereby making it easier for weak pain stimuli to be relayed to the brain. Inhibitory neurotransmission onto pain sensing neurons is largely mediated by the alpha3 glycine receptor subunit that is not found anywhere else in the body. Very little is known about the physiological and pharmacological properties of these receptors. We hypothesise that drugs that increase the activation of alpha3 glycine receptors may provide a novel treatment for pain. This project will firstly identify new drugs that can increase the activation of these receptors. It will then test whether these drugs are likely to work in vivo. The project will also establish why these receptors are found only on pain neurons. Together, this information will establish whether alpha3 glycine receptors represent a promising new therapeutic target for inflammatory pain, and will place us in an excellent position to begin the next step of identifying novel therapeutic lead compounds.Read moreRead less
Structure-function Studies Of Ion Permeation And Selectivity In Recombinant Glycine Receptor Channels
Funder
National Health and Medical Research Council
Funding Amount
$331,300.00
Summary
Ligand-gated ion channels (LGICs) are members of a superfamily of receptor channels, with very significant structural and functional similarities, which play a major role in fast synaptic neurotransmission within the brain and spinal cord, and underlying the complex behaviour of the nervous system, but when dysfunctional can result in major neurological problems. Glycine is one of the two most important inhibitory neurotransmitters in the central nervous system. Impaired glycine-mediated neurotr ....Ligand-gated ion channels (LGICs) are members of a superfamily of receptor channels, with very significant structural and functional similarities, which play a major role in fast synaptic neurotransmission within the brain and spinal cord, and underlying the complex behaviour of the nervous system, but when dysfunctional can result in major neurological problems. Glycine is one of the two most important inhibitory neurotransmitters in the central nervous system. Impaired glycine-mediated neurotransmission underlies a range of inherited neurological diseases and already, it has been shown that the human disorder, familial Startle disease (hyperekplexia) occurs because of point mutations that have impaired the permeation and activation of the glycine receptor (GlyR). Similarly, certain epilepsies are now known to be caused by mutations in, or close to, the channel region in the excitatory acetylcholine receptors (AChRs), which affect channel activation and ion permeation. However, because of their very significant structural and functional similarities, information obtained in one member of the LGIC family of receptors has strong potential application to the other members and the GlyR with its simpler structure has certain advantages for investigation. The first aim of this project is to investigate how the molecular biological structure of these ion channels controls permeation, how it affects how different ions are selectively allowed to move through it and how it affects channel activation. A second related aim is to learn more about the process of desensitization of GlyR receptors, whereby a sustained presence of a high concentration of agonist can cause a reduction in receptor response. A third aim is to specifically investigate the mechanisms underlying the mode of molecular disruption resulting from two new Startle disease mutations, which, in addition to their own inherent clinical value, can also give general information about receptor function.Read moreRead less