Methods for diagnosing and identifying modulators of membrane potentials in bipolar disorder and attention deficit hyperactivity disorder

摘要

The present invention provides methods to modulate key elements along the DAG signaling pathway as well as a diagnostic assay, device and methods of using the same to diagnose bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD). Methods to identify diagnostic markers and drug targets for BD and ADHD. Methods of identifying effective compounds responsible for membrane potentials and excitabilities influencing bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD). Methods of identifying an effective compound that modulates the activity of Ca2+/CaM enzyme and compounds involved in changing the K+ gradient across the plasma membrane thereby increasing or decreasing the membrane potential ratio (MPR™) values. The invention provides methods of identifying a compound that modulates the activity of PKC which is an important protein of the DAG signaling pathway. Methods of identifying a compound that modulates DAG and its related enzymes along the DAG signaling pathway are provided. These compounds decrease or increase the membrane potential ratio (MPR™) in BD and ADHD patients.

主权项

1. A method of identifying an agent for treatment of bipolar disorder (BD) comprising:
combining a first population of human BD patient cells comprising cells that express human calcium-activated potassium-channels hSK4, with a test agent suspected of altering human calcium-activated potassium channels hSK4 activity; obtaining a test ratio of a mean membrane potential of the first population of human BD patient cells incubated in vitro in the presence of the test agent and in the absence of K+, to a mean membrane potential of a second population of the human patient cells incubated in vitro in the absence of the test agent and the presence of K+ or absence of K+; comparing the test ratio to (a) and/or (b): (a) a control ratio of a mean membrane potential from control human cells known to not have BD comprising cells that express human calcium-activated potassium-channels hSK4, incubated in vitro in the presence of an agent that alters human calcium-activated potassium channels hSK4 activity and in the absence of K+, to a mean membrane potential of the control human cells incubated in vitro in the absence of the agent that alters human calcium-activated potassium channels hSK4 activity and in the presence of K+ or absence of K+, (b) a bipolar control ratio of a mean membrane potential from bipolar control human cells known to have BD comprising cells that express human calcium-activated potassium-channels hSK4, incubated in vitro in the presence of the agent that alters human calcium-activated potassium channels hSK4 activity and in the absence of K+, to a mean membrane potential of the bipolar control human cells incubated in vitro in the absence of the agent that alters human calcium-activated potassium channels hSK4 activity and in the presence of K+ or absence of K+; wherein when: (1) the test ratio is not significantly different from the control ratio of (a), (2) the test ratio is increased towards the control ratio in comparison to the bipolar control ratio of (b), or (3) the test ratio is increased in comparison to the bipolar ratio of (b), the test agent modulates the mean membrane potential in BD patients.