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Purinergic modulation of synaptic transmission in central & peripheral nervous system

Ziel

In the current project we will investigate the role of purinergic receptors in synaptic transmission at the neuromuscular junction and in the central nervous system. For neuromuscular transmission we will study the effects of ATP on cholinergic synapses in vertebrates and to compare this to its effects on glutamatergic synapses in insects. In the mammalian brain we will concentrate on the recently described purinergic synapse in the hippocampus. Interestingly the two systems have much in common, particularly the likelihood of interaction between purinergic and nicotinic receptors. The labs involved are particularly well suited to further the above objectives in both the peripheral and central nervous systems as well as to compare these systems in a way that has not been previously discussed.

The research activity will be directed to:
To investigate the mechanisms responsible for feedback inhibition by ATP and adenosine at the neuromuscular junction. Is there a modulatory effect of purines on non-quantal transmitter release?
To evaluate of ATP breakdown at the neuromuscular junction
To study the presynaptic and postsynaptic effects of ATP and adenosine during the remodelling processes
To examine the cross-talk between P1 and P2 receptors in transmitter release at the neuromuscular junction;
To analyse the modulation of P1 and P2 receptors by neuropeptides such as CGRP and substance P on chromaffin cells and the related PC12 cells;
To investigate cross-talk between ACh and ATP receptors PC12 cells;
To elucidate the role of purinergic component of synaptic transmission in the induction and expression of short and long-term changes in the synaptic efficacy. To determine the contribution of the ATP-mediated component of synaptic transmission and to investigate the participation of P2 purinoreceptors in the intracellular calcium signalling in the hippocampal neurons;
To determine the P2X receptor subunit(s) which underlie the purinergic synapse in the hippocampus;
To examine the cross talk between ACh and ATP receptors in synaptic transmission in the hippocampus both functionally and in terms of receptor colocalisation;
To examine the colocalisation of ACh and ATP receptors in the neuromuscular junction and compare this to the hippocampal findings
We expect that the results of this project will elucidate the subtype, transduction mechanism and effector proteins responsible for direct feedback inhibition by ATP of neurotransmitter release from motor nerve endings of vertebrates and insects. Similarly in the hippocampus we will have elucidated the subtype and subcellular localisation of the synaptic P2X receptors. In addition, in the neuromuscular junction, PC12 cells and hippocampus we will have investigated the interaction of nicotinic and purinergic receptors. Finally the influx of calcium through P2X receptor/channels is highly likely to be of major importance to the functional significance of the P2X-receptor mediated synapses and the possible interaction of this calcium influx pathway with the synaptic plasticity widely studied in the hippocampus, will be of great interest.

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University College London
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Adresse
Gower St
WC1E 6BT London
Vereinigtes Königreich

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Beteiligte (4)

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Letzte Aktualisierung: 30 Oktober 2002

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Permalink: https://cordis.europa.eu/project/id/INTAS-1999-01147/de

European Union, 2024