Interaction of NMDA receptor with protein tyrosine phosphatase
OwnerKalev Kask, Thorsten Melcher +1inventors
InventorsKalev Kask, Thorsten Melcher, Nikolich Karoly
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Abstract
The present invention relates to the identification of a binding between NMDA receptor (NMDA-R) subunits and a protein tyrosine phosphatase (PTP). The present invention provides methods for screening a PTP agonist or antagonist that modulates NMDA-R signaling. The present invention also provides methods and compositions for treatment of disorders mediated by abnormal NMDA-R signaling.
Claims19
A method for identifying a modulator of N-methyl-D-aspartate receptor (NMDA-R) signaling activity, comprising detecting the ability of an agent to modulate the phosphatase activity of a protein tyrosine phosphatase with said NMDA-R on a substrate or to modulate the binding of the protein tyrosine phosphatase to NMDA-R, thereby identifying the modulator, wherein the protein tyrosine phosphatase is capable of directly or indirectly dephosphorylating NMDA-R.
A method for identifying an agent as a modulator of NMDA-R signaling, comprising:
- (a) contacting
- (i) the agent
- (ii) a protein tyrosine phosphatase and a protein tyrosine kinase (PTK) that phosphorylates NMDA-R;
- and
- (iii) NMDA-R or a subunit thereof;
- wherein either or both of (ii) and (iii) is substantially pure or recombinantly expressed;
- (b) measuring the tyrosine phosphorylation level of the NMDA-R or subunit;
- (c) comparing the NMDA-R tyrosine phosphorylation level in the presence of the agent with the NMDA-R tyrosine phosphorylation level in the absence of the agent,
- wherein a difference in tyrosine phosphorylation levels identifies the agent as a modulator of NMDA-R signaling.
A method for identifying a nucleic acid molecule that modulates NMDA-R signaling, comprising:
- (a) obtaining a cell culture coexpressing the NMDA-R and a protein tyrosine phosphatase
- (b) introducing a nucleic acid molecule encoding a gene product into a portion of the cells;
- thereby producing cells comprising the nucleic acid molecule;
- (c) culturing the cells in (b) under conditions in which the gene product is expressed;
- (d) measuring the tyrosine phosphorylation level of NMDA-R in the cells in (c) and comparing the level with that of control cells into which the nucleic acid molecule has not been introduced
- wherein a difference in tyrosine phosphorylation levels identifies the nucleic acid molecule as a modulator of NMDA-R signaling.
A method for treating a disease mediated by abnormal NMDA-R-signaling, comprising administering a modulator of a protein tyrosine phosphatase activity, thereby modulating the level of tyrosine phosphorylation of NMDA-R.
Dependencies are inferred from the claim text.