SPECIFIC MODIFICATION OF SKELETAL MUSCLE RYANODINE RECEPTOR ACTIVITY
Funder
National Health and Medical Research Council
Funding Amount
$411,000.00
Summary
The project will have implications for muscle fatigue, which is a public health issue in an aging population, and for neuromuscular diseases and muscle weakness. The ryanodine receptor (RyR) calcium release channel regulates changes in calcium concentrations inside the muscle cell that are essential for respiration and movement. Defects in expression of RyRs results in death in utero or at birth. The RyR is also important in many other tissues, where it acts either alone or in combination with a ....The project will have implications for muscle fatigue, which is a public health issue in an aging population, and for neuromuscular diseases and muscle weakness. The ryanodine receptor (RyR) calcium release channel regulates changes in calcium concentrations inside the muscle cell that are essential for respiration and movement. Defects in expression of RyRs results in death in utero or at birth. The RyR is also important in many other tissues, where it acts either alone or in combination with a second type of calcium channel, to regulate the changes in the concentrations of calcium ions within the cell, which are essential for a variety of processes including cardiac contraction, vascular constriction, neuronal activity and immune responses. Despite its importance, little is known about the regulation of the RyR channel opening during contraction in skeletal muscle or the mechanisms of ion movement through its pore. It is often difficult to define the specific role of RyRs in intact tissues because of the lack of specific probes for the channel. The RyR is an obvious target for therapeutic drugs to modify muscle contraction, but has not been used as such because of the lack of specific and reversible drugs. Muscle performance is reduced, and fatigue is rapid, in neuromuscular disease. Performance can be improved by variety of drugs like anabolic steroids which unfortunately have additional adverse actions. The aims of the project are (a) to discover more about the regulation of, and ion conduction pathway through, the skeletal muscle RyR channel, (b) to identify compounds that can be used as specific probes for RyR activity and (c) to identify compounds that might in the future provide the basis for development of the RyR as a therapeutic target.Read moreRead less
Molecular Mechanism And Novel Activators Of Amino Acid And Calcium-sensing Class 3 G-protein Coupled Receptors
Funder
National Health and Medical Research Council
Funding Amount
$519,715.00
Summary
When we eat protein-containing foods, our bodies extract twenty different amino acids for growth and tissue regeneration. Broad-spectrum amino acid sensing receptors detect the increases in blood amino acid levels and respond by triggering the release of biochemical signals. This project will establish the molecular rules by which these receptors work and identify novel activators with potential therapeutic application for the control of growth, tissue regeneration and calcium metabolism.
Novel Aspects Of Angiotensin AT1 Receptor Signalling Pathways
Funder
National Health and Medical Research Council
Funding Amount
$219,750.00
Summary
Hormones are chemicals released into the blood to influence tissue function by binding to specific sites (receptors) located on the cells found in a particular tissue. In general, it has been considered that a specific receptor activates a specific response when bound by the hormone. However, it is now clear that closely related hormones can activate different patterns of response even when they bind the one type of receptor. The full consequence of this phenomenon is still unknown. Its signific ....Hormones are chemicals released into the blood to influence tissue function by binding to specific sites (receptors) located on the cells found in a particular tissue. In general, it has been considered that a specific receptor activates a specific response when bound by the hormone. However, it is now clear that closely related hormones can activate different patterns of response even when they bind the one type of receptor. The full consequence of this phenomenon is still unknown. Its significance will be investigated in this project for important hormones which are involved in blood pressure control. The renin-angiotensin system makes the hormone angiotensin II which increases blood pressure through actions the heart, blood vessels, nerves and kidneys. One particular receptor type, the AT1 receptor, is responsible for the majority of effects of angiotensin II on these tissues and drugs that inhibit the activity of this receptor are very useful therapies for diseases such as hypertension and heart failure. However, Angiotensin III is a second hormone of the renin-angiotensin system that may also have important effects on tissue function when it activates the AT1 receptor. We have evidence that the type of tissue response that results from angiotensin III activated AT1 receptors is different from the response that results from angiotensin II activation of the same receptors. This raises the possibility that the effects of the AT1 receptor in cardiovascular disease might be differentially promoted by the two angiotensins. This project will investigate the mechanisms by which angiotensin II and anagiotensin III can elicit different activation via the AT1 receptor, and will determine the consequences of this differntial activation to tissue function.Read moreRead less
Muscarinic Receptor Signalling, Transglutaminase And Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$518,210.00
Summary
Diabetes is a major and increasing cuase of death and disability in our society. This studies aims to understand the cellular and molecular mechaisms controlling insulin secretion from the pancreas, since defects in this secretion are involved in causing diabetes. The proposed studies are of relevance to both juvenile and adult-onset diabetes, and may lead to new treatment modalities, as well as potentially being relevant to the use of pencreatic islet cell transplantation in the treatment of di ....Diabetes is a major and increasing cuase of death and disability in our society. This studies aims to understand the cellular and molecular mechaisms controlling insulin secretion from the pancreas, since defects in this secretion are involved in causing diabetes. The proposed studies are of relevance to both juvenile and adult-onset diabetes, and may lead to new treatment modalities, as well as potentially being relevant to the use of pencreatic islet cell transplantation in the treatment of diabetes.Read moreRead less
Voltage Dependent Calcium Channels And Vascular Function: Do Microdomains Determine Function?
Funder
National Health and Medical Research Council
Funding Amount
$597,682.00
Summary
Blood flow depends on arterial diameter which can change with contraction of muscle in the vessel wall. Calcium influx through one type of channel in the muscle cells has been considered critical, but drugs targeting these channels have not succeeded in treating the arterial spasm which occurs after stroke and head injury. Our study will investigate the existence and role of other calcium channels in brain arteries. Knowledge gained will likely lead to development of new drug targets for stroke.
Alteration Of Glucose Metabolism By GPCR Activation
Funder
National Health and Medical Research Council
Funding Amount
$444,796.00
Summary
In type 2 diabetes the effect of insulin to stimulate glucose transport in fat cells and skeletal muscle is impaired so there is great interest in identifying insulin-independent mechanisms that increase glucose transport. Several G protein-coupled receptors (GPCRs) regulate glucose transport independently of insulin but the mechanisms involved in these effects are largely unknown. This project investigates how GPCRs regulate glucose homeostasis and will evaluate them as potential treatments.