Interaction of NMDA receptor with the protein tyrosine phosphatase step in psychotic disorders
The present invention relates to the identification of STEP being as involved in signaling pathways relating to psychotic diseases, including schizophrenia, and other disorders in which NMDA receptor dysfunction is implicated. The present invention provides methods for screening STEP inhibitors that modulate NMDA-R signaling. The present invention also provides methods and compositions for treatment of disorders mediated by abnormal NMDA-R signaling.
1 . A method for identifying a therapeutic agent for treatment of schizophrenia, the method comprising:
detecting the ability of an agent to inhibit the phosphatase activity of a STEP isoform on a substrate or to inhibit the binding of the STEP to NMDA-R, thereby
identifying an inhibitor that is useful as a therapeutic agent,
wherein inhibition of STEP increases NMDA-R signaling activity and is therapeutic in the treatment of schizophrenia.
2 . The method according to claim 1 , wherein said agent modulates the dephosphorylation by STEP of a protein kinase in the NMDA-R signaling pathway.
3 . The method according to claim 2 , wherein said kinase is Src.
4 . The method according to claim 2 , wherein said kinase is Fyn.
5 . The method according to claim 2 , wherein said kinase is ERK.
6 . The method of claim 1 , wherein the STEP isoform is human.
7 . The method of claim 1 , wherein the inhibitor is identified by detecting its ability to inhibit the phosphatase activity of the STEP isoform.
8 . The method of claim 1 , wherein the inhibitor is identified by detecting its ability to inhibit the binding of the STEP isoform to the NMDA-R.
9 . The method according to claim 1 , wherein the inhibitor is identified by detecting its ability to modulate the dephosphorylation of NMDA-R by STEP.
10 . A method for treating a neurologic disorder disease associated With abnormal NMDA-R-signaling, comprising administering a modulator of a STEP activity, thereby modulating the level of tyrosine phosphorylation of NMDA-R.
11 . The method according to claim 10 , wherein said neurologic disorder is a psychotic disorder.
12 . The method according to claim 11 , wherein said psychotic disorder is schizophrenia.
13 . The method according to claim 10 , wherein said inhibitor modulates the ability of STEP to dephosphorylate a protein kinase in the NMDA-R signaling pathway.
14 . The method according to claim 13 , wherein said kinase is Src.
15 . The method according to claim 13 , wherein said kinase is Fyn.
16 . The method according to claim 13 , wherein said kinase is ERK.
17 . The method of claim 10 , wherein the inhibitor modulates the ability of STEP to directly or indirectly dephosphorylate NMDA-R.
18 . The method of claim 10 , wherein the inhibitor modulates the ability of STEP to bind to NMDA-R.
19 . The method of claim 10 , wherein the neurological disease is selected from the group consisting of ischemic stroke; head trauma or brain injury; Huntington's disease; Parkinson's disease; spinocerebellar degeneration; motor neuron diseases; epilepsy; neuropathic pain; chronic pain; alcohol tolerance; schizophrenia; Alzheimer's disease; dementia; psychosis; drug addiction; ethanol sensitivity, mild cognitive impairment; and depression.
20 . A method for identifying a therapeutic agent for treatment of schizophrenia, the method comprising:
contacting a test agent with a cell culture;
detecting the surface expression of NMDA-R subunits in said cell culture contacted with said test agent;
detecting the surface expression of NMDA-R subunits on a control cell culture;
comparing surface expression of said NMDA-R subunits between cell culture contacted with said test agents and said control cell culture, thereby
identifying a test agent that increases surface expression of said NMDA-R subunits;
wherein inhibition of STEP increases NMDA-R surface expression and is therapeutic in the treatment of schizophrenia.