Manipulation of neuronal ion channels

Abstract

The present invention provides compositions and methods for the manipulation of ion channels. For example, the present invention relates to Parkinson's and other neurological diseases and conditions, and treatments thereof. In particular, the present invention provides methods of decreasing pathophysiological high frequency neuronal bursts of Parkinson's and other neurological diseases and conditions. Methods of the present invention comprise decreasing Kv3 ion channel activity in fast-spiking neurons, including by decreasing activity of a Kv3.4 protein and by specifically targeting a Kv3.4 protein with an inhibitor.

1 . A method of inhibiting the ability of a fast-spiking neuronal cell to discharge at a high rate, comprising: providing a compound capable of inhibiting Kv3.4 activity to a cell expressing Kv3 channels comprising a Kv3.4 subunit, under conditions such that the high rate of discharge is inhibited. 
     
     
         2 . The method of  claim 1 , wherein said compound is a toxin. 
     
     
         3 . The method of  claim 2 , wherein said toxin comprises BDS-1. 
     
     
         4 . A method of manipulating neuronal ion channels, comprising:
 transfecting a fast-spiking neuronal cell with a vector encoding an siRNA directed against an mRNA encoding a Kv3.4 protein wherein said siRNA is capable of inhibiting Kv3.4 expression in said cell.   
     
     
         5 . The method of  claim 4 , wherein said cell is in vivo. 
     
     
         6 . The method of  claim 4 , wherein said cell is in vitro. 
     
     
         7 . The method of  claim 4 , wherein said cell is isolated ex vivo. 
     
     
         8 . The method of  claim 4 , wherein said cell is a neuronal stem cell. 
     
     
         9 . The method of  claim 4 , wherein said cell is a globus pallidus neuron, a hippocampal interneuron, or a subthalamic neuron. 
     
     
         10 . The method of  claim 7 , further comprising the step of transplanting said cell into a subject. 
     
     
         11 . A composition comprising an siRNA construct capable of inhibiting expression of a Kv3.4 subunit in a neuronal cell. 
     
     
         12 . The composition of  claim 11 , wherein said Kv3.4 subunit is Kv3.4a subunit. 
     
     
         13 . A method for screening for compounds that inhibit the activity of a Kv3.4 protein, comprising
 a) providing:
 i) a cell expressing Kv3.4 protein, and 
 ii) a test compound; and 
   b) detecting the activity of said Kv3.4 protein in the presence of said test compound.   
     
     
         14 . The method of  claim 13 , wherein said test compound comprises a nucleic acid molecule. 
     
     
         15 . The method of  claim 13 , wherein said test compound comprises an antibody directed against said Kv3.4 protein. 
     
     
         16 . The method of  claim 13 , wherein said test compound comprises a small molecule drug.