What is the problem/issue being addressed by COST-ATP?
With almost no exceptions, nucleotides and specifically ATP are present inside all vesicles from all animal species accompanying all kinds of neurotransmitters and hormones, and often they are present as the sole transmitter in some
neurons. Even more, ATP was the first neurotransmitter found in the most ancient forms of life, like Giardia lamblia, which possess ATP-containing vesicles even having neither mitochondria nor Golgi apparatus. ATP is driven inside the vesicles by a transporter –the vesicular nucleotide transporter (VNUT), which has been identified in the neuroendocrine system and the peripheral and central nervous system. Apart from the well-known function of the ATP as the source of energy for active transport, cell signaling or synthesis of DNA and RNA, a recent report by Estévez-Herrera et al. has demonstrated a role for the ATP within the secretory vesicles. This work suggests that intra-vesicular ATP can control the osmotic pressure to regulate the neurotransmitter content, allowing a high concentration of neurotransmitters within the vesicle. This hypothesis has been demonstrated in vitro and in neuroendocrine chromaffin cells. However, this phenomenon has not been explored in neurons of the Central Nervous System nor with other neurotransmitters, besides catecholamines in large dense core vesicles of chromaffin cells. This project tries to unravel the evidence of the co-release of ATP and NT from the same vesicle and its necessary role in allowing the high accumulation of neurotransmitters in SV of the CNS. The overarching goal of this project is to provide answers to several questions currently unsolved, such as: i) Are ATP-containing SV releasable in inhibitory and excitatory neurons of the CNS and where are their places of release? ii) Are ATP and NT transporters co-release from the same vesicle? and iii) Does ATP impact the storage of neurotransmitters in SV?
Why is it important for society?
ATP is one of the most primitive biological molecules that has been used since the earliest times of evolution as an intracellular energy source and as an extracellular signaling molecule in most cells, including neurons. ATP has been identified as a neurotransmitter in both the peripheral and central nervous systems. The involvement of ATP release in the nervous system has been referred to a variety of biological processes, including maintenance of neuron, astrocyte, and microglia function, development of the cerebellar cortex, neuronal differentiation and neuritogenesis, detection of physiological changes in brain pH, and oxygenation, protection against neurotoxicants, or modulation of cognitive processes among others. In addition, purinergic signaling has been related to pathological processes such as sleep disorders, some forms of epilepsy, depression, and worsening of some neurodegenerative diseases. Due to its exceptionally broad spectrum of signaling functions, there is great interest in purinergic signaling, both under physiological and pathophysiological conditions. A better understanding of the release of ATP will help in the field of biomedicine, to identify new targets with therapeutic potential and to develop new therapies for pathological processes in which purinergic signaling participates. Furthermore, these new and specific targets may generate new lines of research in areas such as the application of new diagnoses or treatments for these pathophysiological conditions.
What are the overall objectives?
This project tries to unravel the evidence of the co-release of ATP and NT from the same vesicle and its necessary role in allowing the high accumulation of neurotransmitters in SV of the CNS, divided into three steps.
I) To locate the ATP-containing vesicles and their release sites in excitatory and inhibitory synapses. To study whether there exists a difference in the neuronal distribution of the ATP-containing vesicles within these neurons and the release of the ATP-containing vesicles location of both cell types.
II) To image VNUT-synaptic vesicles to unveil its vesicular co-release. To visualize whether synaptic vesicles can contain both types of neurotransmitter transporter (VGlut/VGAT) and the ATP transporter (VNUT).
III) To establish a role of intravesicular ATP in neurotransmitter accumulation and release.
