Sustaining neuronal communication through bulk endocytosis. Brain activities such as learning and memory rely on the ability of neurons to communicate. This research will improve our understanding of how synaptic vesicles recycle during periods of intense synaptic activity. This is a fundamental process relevant to neuronal communication, insulin release, hormone secretion, and allergic responses in health and disease and therefore has broad significance. This work will enhance Australia's exist ....Sustaining neuronal communication through bulk endocytosis. Brain activities such as learning and memory rely on the ability of neurons to communicate. This research will improve our understanding of how synaptic vesicles recycle during periods of intense synaptic activity. This is a fundamental process relevant to neuronal communication, insulin release, hormone secretion, and allergic responses in health and disease and therefore has broad significance. This work will enhance Australia's existing strength in cell biology and neuroscience and provide high quality training for an undergraduate student and post-doctoral scientist.Read moreRead less
Membrane excitability and cellular calcium regulation in the peripheral nervous system under different (patho)-physiological conditions and in inflammatory disease. Studies of cytokine action on neurons and muscle give new insights into functional responses of the nervous system to systemic inflammation and sepsis. In some countries, sepsis is the third most frequent cause of death following heart attack. Elucidating the pathomechanisms allows to develop therapeutic strategies. Electrophysiology ....Membrane excitability and cellular calcium regulation in the peripheral nervous system under different (patho)-physiological conditions and in inflammatory disease. Studies of cytokine action on neurons and muscle give new insights into functional responses of the nervous system to systemic inflammation and sepsis. In some countries, sepsis is the third most frequent cause of death following heart attack. Elucidating the pathomechanisms allows to develop therapeutic strategies. Electrophysiology, Ca2+ regulation and optical membrane potentiometry allow us to monitor early changes in disease on a (sub)cellular level. Experiments on Ca2+ regulation and ion channel function in muscle with different cholesterol membrane contents will help to understand pathomechanisms in high cholesterol diseases, e.g. obesity, on the membrane level long before cardiovascular effects become prominent.Read moreRead less
Assessing the physiological roles of ubiquitination in regulating neuronal ion channels, receptors and transporters. Significant alterations in the activity neuronal transporters and receptors occur during tissue injury and regeneration as well as in many neurodegenerative disease states. Modulation of the pathways that control these transporters is an emerging therapeutic target, however, the molecular basis of these control mechanisms remain poorly understood. The outcome of this project will ....Assessing the physiological roles of ubiquitination in regulating neuronal ion channels, receptors and transporters. Significant alterations in the activity neuronal transporters and receptors occur during tissue injury and regeneration as well as in many neurodegenerative disease states. Modulation of the pathways that control these transporters is an emerging therapeutic target, however, the molecular basis of these control mechanisms remain poorly understood. The outcome of this project will be a thorough characterisation of a novel regulatory paradigm in neurons that is likely to be crucial for neuronal development and regeneration, and will potentially provide novel therapeutic targets for various neuronal diseases.Read moreRead less
G-protein coupled receptor-mediated calcium signalling in parasympathetic neurons. External chemical stimuli act on specific cell-surface receptors of neurons resulting in an increase in the intracellular calcium ion concentration which acts as a second messenger to alter neuronal excitability. There are, however, many receptors acting through a number of closely related proteins involving complex intracellular signalling pathways which remain poorly understood. This project uses molecular, elec ....G-protein coupled receptor-mediated calcium signalling in parasympathetic neurons. External chemical stimuli act on specific cell-surface receptors of neurons resulting in an increase in the intracellular calcium ion concentration which acts as a second messenger to alter neuronal excitability. There are, however, many receptors acting through a number of closely related proteins involving complex intracellular signalling pathways which remain poorly understood. This project uses molecular, electrical and fluorescence techniques to elucidate the molecular basis for these interactions by identifying the roles individual proteins play in integrating diverse extracellular stimuli and neuronal excitablility in the peripheral nervous system.Read moreRead less
Functional ubiquitination of neuronal voltage-gated sodium channels. Alterations in the electrical properties of excitable cells occur during tissue injury and regeneration as well as many disease states. Preventing or controlling these changes is a key strategic therapeutic aim. It is, however, only through a comprehensive understanding of the molecular mechanisms that regulate cellular excitability that we can identify these therapeutic targets. The major outcome of this project will be a thor ....Functional ubiquitination of neuronal voltage-gated sodium channels. Alterations in the electrical properties of excitable cells occur during tissue injury and regeneration as well as many disease states. Preventing or controlling these changes is a key strategic therapeutic aim. It is, however, only through a comprehensive understanding of the molecular mechanisms that regulate cellular excitability that we can identify these therapeutic targets. The major outcome of this project will be a thorough characterisation of a novel pathway that is potentially crucial in the development, homeostasis and regeneration of the nervous system. Disruption of normal function of this system may underlie the hyperexcitability observed in mannu neurodegenerative conditions.Read moreRead less
Glycerotoxin, a unique tool to investigate the dynamic interactions between N-type Ca2+ channels and the exo-endocytic machinery. Communication between neurons relies on exocytosis, a process in which synaptic vesicles containing a neurotransmitter release their content in the extracellular synaptic cleft. We have recently discovered a unique neurotoxin called glycerotoxin (GLTx), which selectively activates Ca2+ channels (Cav2.2), linked with the exocytic machinery in the Central Nervous System ....Glycerotoxin, a unique tool to investigate the dynamic interactions between N-type Ca2+ channels and the exo-endocytic machinery. Communication between neurons relies on exocytosis, a process in which synaptic vesicles containing a neurotransmitter release their content in the extracellular synaptic cleft. We have recently discovered a unique neurotoxin called glycerotoxin (GLTx), which selectively activates Ca2+ channels (Cav2.2), linked with the exocytic machinery in the Central Nervous System. GLTx provide a new tool to further dissect the role of Cav2.2 in controlling neurotransmitter release. GLTx also greatly facilitates synaptic vesicle recycling, suggesting an unexpected link between Cav2.2 activation and the compensatory endocytic machinery. Our goal is to investigate functional coupling between Cav2.2 and the exo- and endocytic machineries using GLTx.Read moreRead less
Conantokin selectivity for heteromeric N-methyl-D-aspartate (NMDA) receptors. NMDA receptors are ligand gated ion channels formed by heterogeneous population of subunits with distinct pharmacological and biophysical properties. The heterogeneic receptors are differentially expressed during development and play an important role in many physiological and pathological processes. Conantokins are toxins isolated from Conus venoms, which target NMDA receptor subunits with high affinity. The primary g ....Conantokin selectivity for heteromeric N-methyl-D-aspartate (NMDA) receptors. NMDA receptors are ligand gated ion channels formed by heterogeneous population of subunits with distinct pharmacological and biophysical properties. The heterogeneic receptors are differentially expressed during development and play an important role in many physiological and pathological processes. Conantokins are toxins isolated from Conus venoms, which target NMDA receptor subunits with high affinity. The primary goal of this study is to examine the effects of conantokins on the molecular properties of different NMDA receptor subtypes in vivo and in vitro.Read moreRead less
Molecular structure and function of the glycine receptor. This proposal will employ a cutting edge approach to reveal fundamental new insights into the ways that ligand-gated ion channels, and proteins in general, work. The new knowledge and technology developed here will broaden and strengthen Australia's research expertise across a number of basic scientific disciplines. The results will also have relevance to human health. Glycine receptors have an essential role in brain function and are ....Molecular structure and function of the glycine receptor. This proposal will employ a cutting edge approach to reveal fundamental new insights into the ways that ligand-gated ion channels, and proteins in general, work. The new knowledge and technology developed here will broaden and strengthen Australia's research expertise across a number of basic scientific disciplines. The results will also have relevance to human health. Glycine receptors have an essential role in brain function and are targets for anaesthetics and drugs of abuse. GlyRs are also important in modulating pain sensation by the brain. New insights into how natural agonists and drugs affect ion channel structure and function may lead to novel therapeutic opportunities and improved drug structure predictions.Read moreRead less
Determinants of Expression, Assembly and Function of the Noradrenaline Transporter. The noradrenaline transporter protein that is the focus of this project is important for mental health because it belongs to the family of proteins where psychostimulants, such as cocaine, and drugs used in the treatment of depression act. The project will lead to exciting advances in our understanding of how the structure of this protein controls its functions, and potentially to the design of better antidepress ....Determinants of Expression, Assembly and Function of the Noradrenaline Transporter. The noradrenaline transporter protein that is the focus of this project is important for mental health because it belongs to the family of proteins where psychostimulants, such as cocaine, and drugs used in the treatment of depression act. The project will lead to exciting advances in our understanding of how the structure of this protein controls its functions, and potentially to the design of better antidepressant drugs and to the design of drugs to prevent the effects of cocaine.Read moreRead less
Alpha-Conotoxins: Selective Probes For Nicotinic Receptor Subtype Structure And Function. Marine snails from the waters off the Australian coast produce an amazing variety of mini-proteins in their venoms called conotoxins that they use to capture prey. These conotoxins bind very specifically to receptors in our body associated with the transmission of nerve signals. We will use natural and synthetically modified conotoxins to selectively block particular types of neuronal 'receptors' to gain a ....Alpha-Conotoxins: Selective Probes For Nicotinic Receptor Subtype Structure And Function. Marine snails from the waters off the Australian coast produce an amazing variety of mini-proteins in their venoms called conotoxins that they use to capture prey. These conotoxins bind very specifically to receptors in our body associated with the transmission of nerve signals. We will use natural and synthetically modified conotoxins to selectively block particular types of neuronal 'receptors' to gain a greater understanding of how the nervous system functions. This knowledge will help in the design of new drugs to treat a variety of diseases and disorders. Essentially we will use a chemical armoury developed by the cone snail to design state-of-the-art mini-protein drugs.Read moreRead less