Compositions and methods for modulation of DARPP-32 phosphorylation

A method of identifying a compound that modulates the activity of a serotonergic intracellular signaling pathway molecule in a cell or tissue of interest comprising:

• (a) determining a first level of the activity of the molecule in said cell or tissue;
• (b) contacting said cell or tissue with a test compound;
• and
• (c) determining a second level of activity of the molecule in said cell or tissue, wherein a difference in said first level and said second level of activity of the molecule is indicative of the ability of said test compound to modulate activity a serotonergic intracellular signaling pathway.

A method of identifying a compound that modulates the activity of CK1, Cdk5, AMPA receptor, PP-1, PP2C, PP2B and/or PP2A in a serotonergic intracellular signaling pathway a in a cell or tissue of interest comprising:

• (a) determining a first level of CK1, Cdk5, AMPA receptor, PP-1, PP2C, PP2B and/or PP2A activity in said cell or tissue;
• (b) contacting said cell or tissue with a test compound;
• and
• (c) determining a second level of CK1, Cdk5, AMPA receptor, PP-1, PP2C, PP2B and/or PP2A activity, respectively, in said cell or tissue, wherein a difference in said first level and said second level of CK1, Cdk5, AMPA receptor, PP-1, PP2C, PP2B and/or PP2A activity is indicative of the ability of said test compound to modulate CK1, Cdk5, AMPA receptors, PP-1, PP2C, PP2B and/or PP2A.

A method for identifying an agent to be tested for an ability to treat a 5-HTR-related or DA-related disorder in a patient in need of such treatment comprising:

• (a) contacting a potential agent with CK1 and Ser137-dephosphorylated DARPP-32;
• and
• (b) detecting the amount of phosphorylation of Ser137-dephosphorylated DARPP-32;
• wherein the agent is identified if an increase in the phosphorylation of Ser137-dephosphorylated DARPP-32 is detected in the presence of the potential agent.

A method for identifying an agent to be tested for an ability to treat a 5-HTR-related or DA-related disorder in a patient in need of such treatment comprising:

• (a) contacting a potential agent with Cdk5 and Thr75-dephosphorylated DARPP-32;
• and
• (b) detecting the amount of phosphorylation of Thr75-dephosphorylated DARPP-32;
• wherein the agent is identified if a decrease in the phosphorylation of Thr75-dephosphorylated DARPP-32 is detected in the presence of the potential agent.

A method for identifying an agent to be tested for an ability to treat a 5-HTR-related or DA-related disorder in a patient in need of such treatment comprising:

• (a) contacting a potential agent with PP-1 and Thr34-phosphorylated DARPP-32;
• and
• (b) detecting the amount of dephosphorylation of Thr34-phosphorylated DARPP-32;
• wherein the agent is identified if a decrease in the dephosphorylation of Thr34-phosphorylated DARPP-32 is detected in the presence of the potential agent.

A method for identifying an agent to be tested for an ability to treat a 5-HTR-related or DA-related disorder in a patient in need of such treatment comprising:

• (a) contacting a potential agent with PP2C and Ser137-phosphorylated DARPP-32;
• and
• (b) detecting the amount of dephosphorylation of Ser137-phosphorylated DARPP-32;
• wherein the agent is identified if an decrease in the dephosphorylation of Ser137-phosphorylated DARPP-32 is detected in the presence of the potential agent.

A method for identifying an agent to be tested for an ability to treat a 5-HTR-related disorder or DA-related in a patient in need of such treatment comprising:

• (a) contacting a potential agent with PP2B and Thr34-phosphorylated DARPP-32;
• and
• (b) detecting the amount of dephosphorylation of Thr34-phosphorylated DARPP-32;
• wherein the agent is identified if a decrease in the dephosphorylation of Thr34-phosphorylated DARPP-32 is detected in the presence of the potential agent.

A method for identifying an agent to be tested for an ability to treat a 5-HTR-related or DA-related disorder in a patient in need of such treatment comprising:

• (a) contacting a potential agent with PP2A and Thr75-phosphorylated DARPP-32;
• and
• (b) detecting the amount of dephosphorylation of Thr75-phosphorylated DARPP-32;
• wherein the agent is identified if an increase in the dephosphorylation of Thr75-phosphorylated DARPP-32 is detected in the presence of the potential agent.

A method for identifying a compound to be tested for its ability to modulate the activity of a dopaminergic intracellular signaling pathway in a cell or tissue of interest comprising:

• (a) determining a first level of CK1, Cdk5, AMPA receptor, PP-1, PP2C, PP2B and/or PP2A activity in said cell or tissue;
• (b) contacting said cell or tissue with a test compound;
• and
• (c) determining a second level of CK1, Cdk5, AMPA receptor, PP-1, PP2C, PP2B and/or PP2A activity, respectively, in said cell or tissue, wherein a difference in said first level and said second level of CK1, Cdk5, AMPA receptor, PP-1, PP2C, PP2B and/or PP2A activity is indicative of the ability of said test compound to modulate the dopaminergic intracellular signaling pathway.

A method of identifying a compound to be tested for its ability to modulate the activity of a serotonergic intracellular signaling pathway in a cell or tissue of interest comprising:

• (a) determining a first level of CK1, Cdk5, AMPA receptor, PP-1, PP2C, PP2B and/or PP2A activity in said cell or tissue;
• (b) contacting said cell or tissue with a test compound;
• and
• (c) determining a second level of CK1, Cdk5, AMPA receptor, PP-1, PP2C, PP2B and/or PP2A activity, respectively, in said cell or tissue, wherein a difference in said first level and said second level of CK1, Cdk5, AMPA receptor, PP-1, PP2C, PP2B and/or PP2A activity is indicative of the ability of said test compound to modulate the serotonergic intracellular signaling pathway.