Computational Study Of Selectivity, Gating And Mutation In The Acetylcholine Receptor And Potassium Channels
Funder
National Health and Medical Research Council
Funding Amount
$301,393.00
Summary
One way cells in living organisms communicate with each other is via the passage of charged particles across the cell membrane. This takes place through ion channels, large protein molecules that span the membrane and allow small molecules or ions to pass through a central pore. Malfunction of ion channels is known to underlie a variety of disorders including epilepsy, hypertension, kidney disease, heart attack, deafness. Channels also provide promising targets for making new broad spectrum anti ....One way cells in living organisms communicate with each other is via the passage of charged particles across the cell membrane. This takes place through ion channels, large protein molecules that span the membrane and allow small molecules or ions to pass through a central pore. Malfunction of ion channels is known to underlie a variety of disorders including epilepsy, hypertension, kidney disease, heart attack, deafness. Channels also provide promising targets for making new broad spectrum antibiotics and antivirals. This project aims to study two important types of ion channel: acetylcholine receptors that convey signals between nerve and muscle cells, and potassium channels that regulate the nerve impulses themselves. The binding of the neurotransmitter acetylcholine released from a nerve cell to acetylcholine receptors in the muscle cell prompts the opening of a cation conductive pore. The resulting influx of ions initiates a cascade of events ending in the contraction of the muscle fibre. However, the way in which this channel opening is initiated and how ions move into the muscle cell remain to be determined. Potassium channels are primarily used to rapidly 'switch off' nerve impulses so that subsequent messages can be passed through the nerve cell. To do this they have to be highly discriminatory, allowing only potassium to pass across the cell membrane and not sodium that would initiate another impulse. Although we now know what these tiny proteins look like, it is not clear how they differentiate between types of ions while still allowing many millions to pass each second. We will use computer simulations to study how these two type of channel open and close, and how they discriminate between different ion types. Using sophisticated computational techniques on Australia's most powerful supercomputers we aim to elucidate this fundamental area of human biology in the hope of deriving treatments for some debilitating neuromuscular diseases.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
Role Of Calcium Channels And Small-conductance Potassium Channels In Myenteric Neurons
Funder
National Health and Medical Research Council
Funding Amount
$131,717.00
Summary
This proposal will investigate the electrical properties of neurons in the wall of the intestine that control movements of the bowel. These neurons form an extensive network that runs the length of the gastrointestinal tract and control mixing and propulsion of food along the intestine. We will determine the basic electrical properties of these neurons and investigate why some of them transmit signals in a continuous manner while others transmit signals intermittently and how these patterns of a ....This proposal will investigate the electrical properties of neurons in the wall of the intestine that control movements of the bowel. These neurons form an extensive network that runs the length of the gastrointestinal tract and control mixing and propulsion of food along the intestine. We will determine the basic electrical properties of these neurons and investigate why some of them transmit signals in a continuous manner while others transmit signals intermittently and how these patterns of activity fit into the overall activity of the gut. This study will build on a large body of data obtained from our laboratory that has shown that some of these neurons act as sensors of the presence-absence of food in the intestine while others send signals to the muscle in the wall of the intestine to either relax or contract it so that the food can be processed properly. By knowing what makes these neurons different from each other we will be able to understand what goes wrong in functional bowel disorders where motility is affected, resulting in pain and discomfort.Read moreRead less
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.