Project Details
Projekt
FOR 748: Neuronal and Glial P2 Receptors; Molecular Basis and Functional Significance
Subject Area
Medicine
Term
from 2007 to 2014
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 22935240
Nucleotides are energy storing molecules within cells but also serve as extracellular signalling entities. Especially neurons and glial cells of the peripheral and central nervous system communicate via ATP/ADP or UTP/UDP. Extracellular nucleotides activate two classes of membrane receptors belonging to the P2X and P2Y subtypes. P2X receptors form a family of seven subunits (P2X1-P2X7). The receptors occur as homo- or heteromeric assemblies of three subunits in the cell membrane, where they surround the central pore of a ligand-gated cationic channel. So far the P2Y family comprises of ten subtypes; eight of them are present in human tissues. All P2Y receptors couple through various heteromeric G proteins to the usual second-messenger cascades.
The aim of the Research Unit is to investigate P2X and P2Y receptors at neurons, glial cells and their common precursor cells. We intend to elucidate the structure, assembly, second-messenger mechanisms and interaction pathways of these receptors. Since a number of cells in the organism are endowed with both P2X and P2Y receptors and these receptors may interact in numerous ways, the two receptor-types have to be investigated as complementary entities.
A Research Unit with only eight projects will of course not be able to deal with all aspects of P2 receptor research. Therefore, we will concentrate ourselves on the following subjects:
(1) At the molecular level, we will focus on P2X rather than P2Y receptors because of their unique architecture distinct from conventional ligand-gated ion channels. We will search for the structural determinants of certain functional traits. In the case of P2Y receptors we aim at unravelling the reasons of the agonist promiscuity of the P2Y12, P2Y13 and P2Y14 subtypes. These investigations have important consequences for the deorphanisation of new P2Y-like receptors.
(2) At the functional level, we will concentrate ourselves on P2X and P2Y receptors in neurons and glial cells (astrocytes, Müller cells, microglia) as well as their common precursors.
Although all projects intend to investigate the function of P2 receptors, some of them will put particular emphasis on recombinant receptors, whereas other ones will focus on native receptors situated either at single cells or at cells integrated in tissues of the peripheral or central nervous system. As a consequence of these investigations we will hopefully improve our knowledge on the involvement of P2 receptors in retinal damage, Parkinson's disease and neurodegenerative illnesses.
The aim of the Research Unit is to investigate P2X and P2Y receptors at neurons, glial cells and their common precursor cells. We intend to elucidate the structure, assembly, second-messenger mechanisms and interaction pathways of these receptors. Since a number of cells in the organism are endowed with both P2X and P2Y receptors and these receptors may interact in numerous ways, the two receptor-types have to be investigated as complementary entities.
A Research Unit with only eight projects will of course not be able to deal with all aspects of P2 receptor research. Therefore, we will concentrate ourselves on the following subjects:
(1) At the molecular level, we will focus on P2X rather than P2Y receptors because of their unique architecture distinct from conventional ligand-gated ion channels. We will search for the structural determinants of certain functional traits. In the case of P2Y receptors we aim at unravelling the reasons of the agonist promiscuity of the P2Y12, P2Y13 and P2Y14 subtypes. These investigations have important consequences for the deorphanisation of new P2Y-like receptors.
(2) At the functional level, we will concentrate ourselves on P2X and P2Y receptors in neurons and glial cells (astrocytes, Müller cells, microglia) as well as their common precursors.
Although all projects intend to investigate the function of P2 receptors, some of them will put particular emphasis on recombinant receptors, whereas other ones will focus on native receptors situated either at single cells or at cells integrated in tissues of the peripheral or central nervous system. As a consequence of these investigations we will hopefully improve our knowledge on the involvement of P2 receptors in retinal damage, Parkinson's disease and neurodegenerative illnesses.
DFG Programme
Research Units
Projects
- Characterization of affinity-tagged fluorescent P2X and P2Y receptors in BAC transgenic mice in health and disease (Applicants Franke, Heike ; Schmalzing, Günther )
- Expression, function and interaction of purinergic receptor subtypes on glial cells of the retina (Applicant Reichenbach, Andreas )
- Functional specificity of ADP-(P2Y12)-like receptors (Applicant Schulz, Angela )
- Generation of transgenic mice to investigate the expression patterns, protein interactions and physiological functions of P2X4, P2X6 and P2X7 receptors (Applicant Nicke, Annette )
- Human 5'-NT und P2X receptors: Structure, function and inhibitor design (Applicant Sträter, Norbert )
- Involvement of P2 receptors in the modulation of nociceptive afferent stimuli (Applicants Illes, Peter ; Riedel, Thomas )
- Nucleotide receptors govern proliferation and differentiation of human neural stem cells (Applicant Zimmermann, Herbert )
- Pharmacological modulation of P2X receptors by approved drugs and natural compounds (Applicant Schaefer, Michael )
- The interplay between P2 and P1 receptors to control microglial function (Applicant Kettenmann, Helmut )
- The P2X receptor binding domain: structure, conformational changes and coupling to the ion channel (Applicant Nicke, Annette )
- Z-Project (coordination and central funds) (Applicant Schöneberg, Torsten )
Spokesperson
Professor Dr. Torsten Schöneberg
