Deciphering The Molecular Steps Leading To The Potentiation Of Neuronal Exocytosis By Arachidonic Acid
Funder
National Health and Medical Research Council
Funding Amount
$273,000.00
Summary
Release of hormones and neurotransmitters relies on a process called exocytosis which involves SNARE proteins: syntaxin1A and SNAP-25 on the target plasma membrane and VAMP on the vesicular membrane. Availability of the t-SNARE on the plasma membrane is believed to play a major role in controlling the amount of exocytosis. Syntaxin1A bound to Munc18 constitute an 'unproductive-reserve' pool of closed Syntaxin that cannot interact with SNAP-25. Intracellular messengers capable of releasing Syntax ....Release of hormones and neurotransmitters relies on a process called exocytosis which involves SNARE proteins: syntaxin1A and SNAP-25 on the target plasma membrane and VAMP on the vesicular membrane. Availability of the t-SNARE on the plasma membrane is believed to play a major role in controlling the amount of exocytosis. Syntaxin1A bound to Munc18 constitute an 'unproductive-reserve' pool of closed Syntaxin that cannot interact with SNAP-25. Intracellular messengers capable of releasing Syntaxin1A from Munc18 thereby making it available to interact with SNAP-25, are foreseen to play a major role in potentiating exocytosis - a process with ramification for memory and learning. We have identified arachidonic acid, a lipidic messenger which fullfil this role. For the first time we are in a position to manipulate at the molecular level different pools of SNARE proteins with direct implications for our understanding of the mechanism of secretion. Very few models are currently available to understand how learning and memory occur in the brain. Our research points to a new direction: the amount of 'active' and 'unproductive-reserve' pools of SNARE proteins present on the plasma membrane of neurosecretory cells are in dynamic equilibrium and arachidonic acid, a second messenger capable of trans-synaptic action, can modify this equilibrium resulting in an increase of the amount of 'active' SNARE thereby potentiating the amount of transmitter-hormone released by exocytosis. Importantly, this research lays the basis for a dynamic view of the secretory mechanism with important implications for treatment of diseases such as diabetes and neurodegenerative diseases. Our hope is that by understanding at the molecular level how secretory cells regulate the amount of their secretion, we will be in a position to modify these parameters in order to counteract illnesses of the nervous system.Read moreRead less
Neuroendocrine Functions Of PrRP, A Novel Hypothalamic Peptide
Funder
National Health and Medical Research Council
Funding Amount
$183,928.00
Summary
This project investigates the role of a newly discovered chemical (peptide) that is found in a part of the brain called the hypothalamus which regulates the activity of the pituitary gland. The hypothalamus and pituitary gland work together to control many of the body?s essential processes such as growth, metabolism and reproduction. Some human diseases are caused by abnormalities of the hypothalamus and pituitary gland while many other diseases affect the functions of these glands, leading to w ....This project investigates the role of a newly discovered chemical (peptide) that is found in a part of the brain called the hypothalamus which regulates the activity of the pituitary gland. The hypothalamus and pituitary gland work together to control many of the body?s essential processes such as growth, metabolism and reproduction. Some human diseases are caused by abnormalities of the hypothalamus and pituitary gland while many other diseases affect the functions of these glands, leading to widespread complications such as weight loss, wasting, abnormal immune responses, infertility or failure of lactation. While many of the hormones and chemicals of the hypothalamus and pituitary gland have been extensively studied, recent advances in molecular biology have led to the discovery of new chemicals that may have important regulatory functions. One of these newly discovered substances which was named Prolactin-Releasing Peptide or PrRP is the topic of this project. PrRP will be tested in a series of experiments in animals in order to determine how important it is in regulating the pituitary gland, particularly in stress and during lactation which are conditions when PrRP could be secreted. It is hoped that this research will lead to a more detailed understanding of how the reproductive and endocrine system are controlled in humans and to new methods for the manipulation of these systems under normal and disease conditions.Read moreRead less
This project examines the mechanism of descent of the testis, which when abnormal, leads to the common anomaly in children of undescended testes. Our long-term aims is to find a non-surgical treatment for undescended testes, and these studies will significantly aid in that goal. We will look at a completely new testicular hormone as well as a molecule released from nerves to determine their exact role in the mechanism. This project should allow us to understand finally one of the unresolved puzz ....This project examines the mechanism of descent of the testis, which when abnormal, leads to the common anomaly in children of undescended testes. Our long-term aims is to find a non-surgical treatment for undescended testes, and these studies will significantly aid in that goal. We will look at a completely new testicular hormone as well as a molecule released from nerves to determine their exact role in the mechanism. This project should allow us to understand finally one of the unresolved puzzles of the anatomical differences between males and females.Read moreRead less
Hormone Transport By Alpha-2-Macroglobulin: Novel Roles In Regulating Hormone Activity
Funder
National Health and Medical Research Council
Funding Amount
$602,857.00
Summary
Alpha-2-macroglobulin is a large protein in the blood known to bind and transport numerous hormones in the circulation. Our previous studies published in BLOOD (2009) and JBC (2013) have discovered an important role for this molecule in the transport and regulation of a peptide hormone. The studies proposed in this application have important implications for understanding new roles of alpha-2-macroglobulin in hormone binding and regulating the activity of hormones in disease states.