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Title:  Regulation of neuronal function through metabotropic glutamate receptor signaling pathways
United States Patent: 
7,129,073
Issued: 
October 31, 2006

Inventors: 
Liu; Feng (Plainsboro, NJ), Nairn; Angus C. (Guilford, CT), Greengard; Paul (New York, NY)
Assignee: 
The Rockefeller University (New York, NY)
Appl. No.: 
10/175,190
Filed: 
June 18, 2002


 

Pharm Bus Intell & Healthcare Studies


Abstract

The present invention provides methods and compositions for modulating the activities of metabotropic glutamate receptor intracellular signaling molecules. The present invention provides methods and compositions for modulating the activities of casein kinase I and/or cyclin-dependent kinase 5 in cells or tissues. The present invention provides methods of modulating the function of calcium channels in cells or tissues. The present invention provides methods of treating calcium channel dysfunction. The present invention provides methods of identifying agents that modulate the activities of the metabotropic glutamate receptor intracellular signaling molecules casein kinase I and/or cyclin-dependent kinase 5 for use in such treatments.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based in part on the surprising discovery, on the part of the inventors, that both casein kinase I ("CKI" or "CK1") and cyclin-dependent kinase 5 (Cdk5) are part of the metabotropic glutamate receptor (mGluR) signaling pathway in neuronal tissues.

The present invention provides a method for modulating casein kinase I ("CKI" or "CK1") and/or cyclin-dependent kinase 5 ("Cdk5," "cdk5" or "CDK5") activity in a cell or tissue of interest, comprising contacting the cell or tissue of interest with an effective amount of a compound that alters the activity of a metabotropic glutamate receptor (mGluR) intracellular signaling molecule, wherein contact of the cell or tissue with the compound results in a modulation of the activity of casein kinase I or cyclin-dependent kinase 5.

The present invention provides a method for regulating activity of calcium channels comprising administering (for example, to an individual, patient or animal) an effective amount of a compound of the invention, for example, a compound identified by the methods of the invention, wherein the compound modulates the activity of casein kinase I (CKI) and/or cyclin-dependent kinase 5 (Cdk5), and wherein modulation of CKI or Cdk5 activity results in an alteration in the activity of calcium channels in the neuron. In a specific embodiment, the calcium channels are in an excitable cell, e.g., a neuron. In another embodiment, the method involves administration of a mGluR agonist in order to increase activity of CKI and Cdk5 and thereby alter activity of calcium channels.

The present invention provides, in vivo, in situ, and in vitro, methods of identifying an agent, drug or compound for modulating the activity of casein kinase I (CKI) and/or cyclin-dependent kinase 5 (Cdk5) in a cell or tissue of interest. Such methods can be used alone or in conjunction with each other. In one embodiment, the method comprises determining a first level of casein kinase I and/or cyclin-dependent kinase 5 activity in a cell or tissue of interest; contacting the cell or tissue with a test compound; and determining a second level of casein kinase I and/or cyclin-dependent kinase 5 activity in the cell or tissue, wherein a difference in the first level and the second level of casein kinase I and/or cyclin-dependent kinase 5 activity is indicative of the ability of the test compound to modulate casein kinase I and/or cyclin-dependent kinase 5 activity.

In another embodiment, the method comprises determining a first level of casein kinase I and/or cyclin-dependent kinase 5 activity in a cell or tissue of interest; determining a first level of calcium channel activity in the cell or tissue; contacting the cell or tissue with a test compound; determining a second level of casein kinase I and/or cyclin-dependent kinase 5 activity in the cell or tissue; and determining a second level of calcium channel activity in the cell or tissue, wherein a difference in the first level and the second level of casein kinase I and/or cyclin-dependent kinase 5 activity and a difference in the first level and the second level of calcium channel activity are indicative of the ability of the test compound to modulate the activity of calcium channels.

The present invention also provides in vivo methods of identifying agents that can modulate the activity of CKI or Cdk5. Such methods can be employed alone or in conjunction with in vitro and in situ methods as disclosed herein. One such method comprises administering the agent to a non-human mammal. The amount (and/or rate) of activation of CKI and/or Cdk5 is then determined. An agent is identified as capable of modulating the activity of CKI and/or Cdk5 when the amount (and/or rate) of activation is increased or decreased in the presence of the agent relative to in the absence of the agent. In preferred embodiments, the non-human mammal is a rodent. In a more preferred embodiment, the rodent is a mouse.

The invention also provides methods of screening potential agents (or drugs or compounds) in order to select an agent that can potentially ameliorate and/or be used in treatment of mGluR-related, CKI-related, Cdk5-related and/or calcium channel-related disorders.

The present invention also provides methods of identifying agents (or drugs or compounds), e.g., drug screening assays, which drugs may be used in therapeutic methods for the treatment of mGluR-related, CKI-related, Cdk5-related and/or calcium channel-related disorders.

The present invention also provides compositions for modulating the activity of casein kinase I (CKI) and/or cyclin-dependent kinase 5 (Cdk5). The invention also provides compositions for modulating the activity of calcium channels via modulation of the activity of casein kinase I (CKI) and/or cyclin-dependent kinase 5 (Cdk5).

The present invention further provides methods for performing rational drug design to develop drugs that can modulate activity of CKI and/or Cdk5 and thereby ameliorate mGluR-related, CKI-relate, Cdk5-related and/or calcium channel-related disorders.

In one embodiment, the invention provides methods of identifying a compound that modulates the activity of cyclin-dependent kinase 5 in a cell or tissue of interest comprising: (a) determining a first level of cyclin-dependent kinase 5 activity in said cell or tissue; (b) contacting said cell or tissue with a test compound; and (c) determining a second level of cyclin-dependent kinase 5 activity in said cell or tissue, wherein a difference in said first level and said second level of cyclin-dependent kinase 5 activity is indicative of the ability of said test compound to modulate cyclin-dependent kinase 5 activity, and wherein modulation of cyclin-dependent kinase 5 activity is regulated by modulation of the activity of metabotropic glutamate receptors.

The present invention also provides diagnostic and therapeutic methods for the treatment of a mGluR-related, CKI-related, Cdk5-related or calcium channel-related disorder, including, but not limited the use of compositions or compounds of the invention in the treatment of a mGluR-related, CKI-related, Cdk5-related or calcium channel-related disorder.

In one aspect, the invention provides a method for treating a neuronal condition characterized by an increase or a decrease in calcium channel activity (e.g., calcium channel currents) comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention to modulate CKI and/or Cdk5 activity, and thus increase or decrease calcium channel activity via modulation of a mGluR signaling pathway. In one embodiment, the mGluR signaling pathway comprises: activation of mGluR1 receptors that stimulate G proteins that are coupled to PLC.beta., activation of the Ca.sup.2+/calmodulin-dependent phosphatase, calcineurin (PP2B), by Ca.sup.2+ released from IP3-sensitive stores, dephosphorylation of the inhibitory autophosphorylation sites on CK1.epsilon. by calcineurin, resulting in an increase in kinase activity.

The present invention provides methods for treating a mGluR-related, CKI-related, Cdk5-related or calcium channel-related disorder in an individual (e.g., a patient) or an animal subject by administering an effective amount of a compound of the invention to modulate CKI and/or Cdk5 activity. In one embodiment, the agent promotes or increases the activity of CKI and/or Cdk5. In another embodiment, the agent inhibits or decreases the activity of CKI and/or Cdk5.

The invention provides methods of administering an agent (or drug or compound) of the invention that can ameliorate a symptom of a mGluR-related, CKI-relate, Cdk5-related and/or calcium channel-related disorder, disease and/or condition in a patient or subject exhibiting the symptom. In certain embodiments, the invention provides methods of administering an agent identified by the methods disclosed herein, that can ameliorate a symptom of a mGluR-related, CKI-related, Cdk5-related or calcium channel-related disorder in a patient or subject exhibiting the symptom. In other embodiments, an agonist of mGluR activity can be used to for treating a mGluR-related, CKI-related, Cdk5-related or calcium channel-related disorder. In yet other embodiments, an antagonist of mGluR activity can be used to for treating a mGluR-related, CKI-related, Cdk5-related or calcium channel-related disorder.

The present invention also provides compositions for modulating the activity of casein kinase I (CKI) and/or cyclin-dependent kinase 5 (Cdk5). The invention also provides compositions for modulating the activity of calcium channels via modulation of the activity of casein kinase I (CKI) and/or cyclin-dependent kinase 5 (Cdk5).

The present invention also provides pharmaceutical compositions of the agents (or drugs or compounds) of the invention disclosed herein. The invention encompasses pharmaceutical compositions for regulating CKI and/or Cdk5 activity, and for diagnosing or treating a mGluR-related, CKI-related, Cdk5-related or calcium channel-related disorder. Because a loss of normal function results in the development of a phenotype of the above-listed diseases or disorders, activation of the metabotropic glutamate receptor (mGluR) signaling pathway, or an increase in CKI and/or Cdk5 activity (e.g., downstream activation) facilitates amelioration of a symptom in individuals exhibiting a symptom of such a disorder.
 


Claim 1 of 7 Claims

1. A method for modulating cyclin-dependent kinase 5 ("Cdk5") activity in a cell or tissue comprising (a) contacting the cell or tissue with an effective amount of a compound that alters the activity of phospholipase C-beta ("PLC.beta."), wherein contact of the cell or tissue with the compound results in a modulation of Cdk5 activity; and (b) comparing the Cdk5 activity in the cell or tissue contacted with the compound that alters the activity of PLC.beta. to the Cdk5 activity in a control cell or control tissue not contacted with the compound that alters the activity of PLC.beta..
 

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If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.

 

 

     
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