Receptor Signalling Through Intracellular Calcium Stores In Chromaffin Cells
Funder
National Health and Medical Research Council
Funding Amount
$461,000.00
Summary
The function of cells in the body is controlled by many hormones and neurotransmitters acting on the cell's surface. Hormones and transmitters mediate their effects by producing chemical signals within the cell that regulate its activities. One key cell signalling chemical is calcium, especially in nerve cells which have developed sophisticated mechanisms for using calcium to control their function. Recently, new levels of complexity have been discovered, both in how cell calcium levels are modi ....The function of cells in the body is controlled by many hormones and neurotransmitters acting on the cell's surface. Hormones and transmitters mediate their effects by producing chemical signals within the cell that regulate its activities. One key cell signalling chemical is calcium, especially in nerve cells which have developed sophisticated mechanisms for using calcium to control their function. Recently, new levels of complexity have been discovered, both in how cell calcium levels are modified by hormones and transmitters and in how these complex calcium signals are used by cells to control their function. This project will investigate how hormones and transmitters can produce different types of calcium signals in nerve cells, and how these signals affect different aspects of the nerve cell's function. In particular, it will establish how two different types of specialised calcium stores within nerve cells are used by different classes of hormone and transmitter, and the distinct cellular functions these two calcium stores can regulate. The results will provide fundamental new information on how nerve cells control their activity and may help identify potential new targets for drugs.Read moreRead less
Molecular Mechanisms That Help Organise Effective Synaptic Transmission.
Funder
National Health and Medical Research Council
Funding Amount
$555,825.00
Summary
This study will test the idea that adhesion molecules alpha4- and beta2-laminin are needed for proper development and function of motor nerve - muscle connections. This study will provide insights into how such molecules control effective nerve-muscle communication, in both health and disease. We also believe that our results will provide the basic knowledge needed for identifying pharmacological targets that could improve such connections, and to promote reconnections between nerve and muscle.
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
The amygdala is an area of the brain that is involved in assigning emotional content to sensory information. Disorders of the amygdala lead to a variety of anxiety-related mental disorders such as panic attacks and post-traumatic stress. This grant will study how the NMDA receptor, which plays a central role in memory formation, works in the amygdala. We will determine the functional role of this receptor in the amygdala and how it may be modified by experience.
Mechanisms Underlying Short- And Long-term Plasticity At The Mossy Fibre -> CA3 Synapse In The Hippocampus
Funder
National Health and Medical Research Council
Funding Amount
$272,750.00
Summary
Synapses, the contacts between brain cells, are extremely plastic. They can become stronger and weaker depending on the activity they experience. The hippocampus, a structure in the brain, is known to be critical to the formation of conscious memories. The plastic nature of the synapse in this structure is thought to underlie learning and memory. Understanding the mechanisms that are responsible for the changes in synaptic strength in the hippocampus are therefore important to our understanding ....Synapses, the contacts between brain cells, are extremely plastic. They can become stronger and weaker depending on the activity they experience. The hippocampus, a structure in the brain, is known to be critical to the formation of conscious memories. The plastic nature of the synapse in this structure is thought to underlie learning and memory. Understanding the mechanisms that are responsible for the changes in synaptic strength in the hippocampus are therefore important to our understanding of learning and memory. This proposal describes a series of experiments that are designed to determine the mechanisms of plastic changes . We hope, that by understanding these mechanisms, we can start to understand how we learn and remember.Read moreRead less
Identification And Function Of Kv7-M-channels In Axons Of Cortical Neurons
Funder
National Health and Medical Research Council
Funding Amount
$324,930.00
Summary
Membrane proteins permeable to potassium ions provide an important break during hyperexcitability of nerve cells in the brain. In this proposal I will study the function of a unique member of potassium channel protein (the M-channel) located at key regions of nerve cells; the axon. The results will provide important insights into the elementary steps of nerve cell excitability, and a better understanding of M-channel related diseases including neonatal epilepsies and chronic nerve pain.
PROBABILITY OF QUANTAL SECRETION AT NEUROMUSCULAR SYNAPSES
Funder
National Health and Medical Research Council
Funding Amount
$334,232.00
Summary
The classical preparation for the study of synaptic transmission is the amphibian neuromuscular junction, for which there is the largest body of experimental data. This synapse was instrumental in the discovery that transmitters are released in packets or quanta, that this occurs at specialized release sites in the nerve terminal, and that receptor molecules on the muscles cells are strategically placed to receive the transmitter. Our work on this synapse has shown that each of these release sit ....The classical preparation for the study of synaptic transmission is the amphibian neuromuscular junction, for which there is the largest body of experimental data. This synapse was instrumental in the discovery that transmitters are released in packets or quanta, that this occurs at specialized release sites in the nerve terminal, and that receptor molecules on the muscles cells are strategically placed to receive the transmitter. Our work on this synapse has shown that each of these release sites have different probabilities for the secretion of a quantum and that this probability is correlated with the width of the release site. More recently we have shown that, whilst the size of a quantum does not vary between adjacent release sites, the area over which the quantum is released does vary between sites. The probability of quantal secretion is proportional to this area, as is the number of vesicles present at the release site. In this project we intend to relate this probability of secretion to the proteins that regulate the release of a quantum and in particular how these proteins interact to determine the time course of increase in probability at a release site after the passage of an impulse. The affects of trains of impulses on this probability are also to be delineated, in particular how the calcium which enters the terminal during these trains determines a long-term enhancement in probability after the train has ceased. This research will provide a molecular description of secretion from motor-nerve terminals.Read moreRead less
Modulation Of Calcium Signalling By Acetylcholine In The Basolateral Amygdala
Funder
National Health and Medical Research Council
Funding Amount
$266,748.00
Summary
The amygdala is an area of the brain involved in assigning emotional significance to sensory stimuli. This grant examines the cellular processes involved in making these associations. Specifically, it studies the relationship between two signalling molecules implicated in association learning, acetylcholine and calcium. This research will test hypotheses of memory formation and provide insight into disorders linked to detrimental emotional associations, such as anxiety and addiction.
Novel Substance P Receptors On Autonomic And Sensory Neurons Regulating The Viscera
Funder
National Health and Medical Research Council
Funding Amount
$447,750.00
Summary
Potentially harmful stimulation of the skin or the internal organs activates sensory nerves that send signals to the brain. These events often are perceived as painful. One chemical messenger transmitting these signals first to the spinal cord, and then to the brain, is a neuropeptide called substance P. During many chronic inflammatory conditions, such as inflammation of the bowel, these signalling pathways are sensitised so that stimuli that previously were not painful now are perceived as pai ....Potentially harmful stimulation of the skin or the internal organs activates sensory nerves that send signals to the brain. These events often are perceived as painful. One chemical messenger transmitting these signals first to the spinal cord, and then to the brain, is a neuropeptide called substance P. During many chronic inflammatory conditions, such as inflammation of the bowel, these signalling pathways are sensitised so that stimuli that previously were not painful now are perceived as painful. This sensitisation has several different causes. One contributing factor seems to be related to a change in the receptor molecules that recognise substance P. Last year we discovered a new type of receptor for substance P, that is prominent in the nerve pathways between the gut and the spinal cord. This novel receptor has important characteristics that are different from the classical substance P receptor. However, we are still largely ignorant about how substance P interacts with these new receptors to modify the activity of nerve cells in sensory pathways. Indeed, we propose that these new receptors are likely to make a significant contribution to the sensitisation that occurs in inflammation. We will use a combination of sophisticated cellular and molecular techniques to study the way in which substance P acts on these novel receptors in nerves regulating the visceral organs. Our results are likely to make a significant contribution to the development and interpretation of rational new therapies for treating chronic diseases of the gastrointestinal tract, such as inflammatory bowel disease (IBD). Our studies will reveal signalling mechanisms that also are likely to be used by substance P more widely in the nervous system, that are relevant to other inflammatory conditions like arthritis, and even some forms of depression.Read moreRead less