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Nucleotides, a novel class of extracellular signalling substances in the nervous system

Objective

To analyze the mechanisms underlying the release of nucleotides from the CNS and target areas.
To identify new P2-purinoceptor subtypes and to synthesize novel P2 receptor subtype ligands, expected to be specific agonists/antagonists.
To investigate the cellular responses to nucleotides and the intracellular signalling cascades in select examples of neural or glial cells.
To characterize the enzymes involved in the extracellular hydrolysis of ATP and ADP.
To reveal the pathological implications of extracellular nucleotides, with particular emphasis on nociception.

Nucleotides, a novel group of signalling substances in the central and peripheral nervous system will be studied. These include ATP, ADP, UTP or the diadenosine polyphosphates Ap3A, Ap4A, Ap5A, and Ap6A. The release of ATP from nerve endings will be characterized including its function via presynaptic receptors as an autocrine substance. The action of nucleotides on their receptors and the induction of intracellular signalling pathways will be studied in select examples such as astrocytes and the sensory hair cells of the inner ear. This includes the differentiation by selective analogues between the various nucleotide receptor subtypes including those for nucleoside 5'-triphosphates and the diadenosine polyphosphates. New P2-receptor subtypes will be identified and isolated. The involvement of ATP and possibly other nucleotides in pathological mechanisms is investigated using nociception as an example. The enzymes that effect the extracellular hydrolysis of nucleotides such as ATP and ADP are characterized in functional and molecular terms. Their sites of expression in the nervous system will be determined using immunocytochemistry. Analogues are developed that differentiate between nucleotide receptor subtypes and that selectively affect either receptors or ecto-nucleotidase. These substances will be the basis for the development of drugs to deal with diseases based on specific faults in the signalling cascade via extracellular nucleotides.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Johann-Wolfgang-Goethe Universität Frankfurt
Address
9,Marie-curie-strasse
60439 Frankfurt-am-main
Germany

Participants (6)

Albert-Ludwigs-Universität Freiburg
Germany
Address
5,Hermann-herder-strasse
79104 Freiburg
Stockholms Universitet
Sweden
Address
21 A,stockholm University
106 91 Stockholm
THE UNIVERSITY OF MILANO
Italy
Address
Via Balzaretti 9
20133 Milano
Universidad Complutense de Madrid
Spain
Address
S/n,universidad Complutense
2840 Madrid
Universidade de Lisboa
Portugal
Address
Avenida Prof. Egas Moniz
1600 Lisboa
University College London
United Kingdom
Address
5,Rowland Hill Street
NW3 2PF London