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Modulation of Potassium Channels by Protein Phosphorylation and Interacting Auxiliary Proteins

Leonard K. Kaczmarek, Yale University

Overview: Our research is focused on potassium channels, Kv3.4 and Slack (KNa1.1), which emerging evidence suggests play a key role in opiate abuse. Both channels are very highly expressed in the amygdala and the striatum, and in dorsal root ganglia (DRG) and the ventral spinal cord. Reduction of the levels of these channels, either by genetic manipulations or in response to injury, results in enhanced pain sensation. We are testing the hypothesis that changes in these channels, and specifically in the cytoplasmic proteins with which these channel subunits interact, lead to abnormal signaling that is activated with opiate treatment.

The MAPK10 (MAP Kinase 10) and the TBK1 (Tank Binding Kinase1)/ ubiquitination/autophagy pathways are both abnormally activated with opioid treatment. We have found that MAPK10 binds directly to the cytoplasmic C-terminal domain of Kv3.4. This channel subunit also forms heteromers with the Kv3.3 subunit. We plan to determine if MAPK10 phosphorylates the channels and map the phosphorylation sites. Most importantly, we plan to determine whether gating of these channels directly alters the activity of this enzyme, a finding that would shed a light on the overactivation of MAPK10 during addition. Parallel experiments will be carried out with TBK1 and with Protocadherin 9 (PCDH9), a Kv3.4 interacting molecule that, when suppressed, causes long-term social and object recognition deficits. We also plan to complete our studies on the interactions of KNa1.1 with several signaling molecules that have been supported by the Yale/NIDA Neuroproteomics Center. This information will be used to test how these interactions are altered by drugs of abuse.