Identifying mechanisms that control slack channel trafficking
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Inflammatory pain is a neural response mechanism to tissue damage that is characterized by dorsal root ganglia (DRG) neuronal hyperexcitability. The involvement of Protein kinase A (PKA) in this process is well-established and is believed to directly cause neuronal hyperexcitability and the symptoms of hyperalgesia observed during inflammatory pain. Activation of the PKA pathway by inflammatory mediators such as prostaglandin E2 (PGE2) leads to changes in ion channel properties in the DRG neurons. Our group previously showed that PKA modulates the membrane expression of Slack channels, a subtype of sodium-activated potassium channels (KNa) that control firing accommodation in DRG neurons. The Slack channel contains a "post synaptic density, drosophila disc large tumor suppressor, zonula occludens-1" (PDZ) binding domain at the end of its C-terminus. PDZ domains are protein-protein interaction segments that act as scaffolds for clustering different signaling complexes that can modulate channel activity. I sought to probe the interactions at the PDZ domain of DRG Slack channels with a peptide consisting of the highly conserved last 10 amino acids of the Slack C-terminus. I showed that the application of the peptide alone to the embryonic DRG neuronal cultures can lead to neuronal hyperexcitability 50% of the time. The peptide acted in a similar manner to PKA phosphorylation and caused Slack channel internalization from the neuronal membrane as determined by membrane biotinylation assays. A scrambled version of the peptide produced no effect. These results suggest that the binding of the Slack channels to a PDZ scaffold is critical in keeping them at the membrane and may prevent the internalization of Slack channels. Identifying and understanding the entities involved in the trafficking of Slack channels and disrupting their activity during inflammation could lead to the development of novel analgesics to treat pain.
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