Novel Modulation of a Dorsal Root Ganglion Potassium Channel by Calcineurin and Protein Kinase C
Voltage-gated K+ (Kv) channels are essential regulators of excitability in the nervous system. Thus, Kv channel dysfunction is often linked to neurological disorders. Unfortunately, missed opportunities to develop effective interventions rest on the lack of understanding of the mechanisms that modulate the expression and function of Kv channels. The Kv3.4 channel is robustly expressed in pain fibers, where it plays a major role in shaping the repolarization phase of the action potential (AP). Kv3.4 loss of function after spinal cord injury is associated with hyperexcitability of pain fibers and the ensuing persistent pain in rats. The work in this thesis utilized a multidisciplinary approach based on electrophysiology, imaging, biochemistry and molecular biology to investigate the mechanisms that modulate functional expression of Kv3.4 channels in neurons of the dorsal root ganglion (DRG), which harbors pain fibers. The main results show that inhibition of the phosphatase, calcineurin (CaN), phenocopies the SCI-induced loss of Kv3.4 current. This effect prolongs the AP and is dependent on previously identified serine phosphorylation sites within the Kv3.4 inactivation domain, where they are also implicated in elimination of fast inactivation. Furthermore, we determined that CaN inhibition after SCI was linked to upregulation of the endogenous regulator of CaN, RCAN1. On a separate effort, we additionally identified protein kinase C epsilon (PKCϵ) as a novel Kv3.4 interacting protein that stabilizes the expression of the Kv3.4 protein, but has no effect on channel gating. This finding is particularly important because it identifies for the first time a molecular component of the previously proposed Kv3.4 signaling complex in DRG neurons. The discoveries resulting from this work not only broaden our understanding of Kv3.4 channel function, dysfunction and modulation but also help identify new approaches to treat persistent pain syndromes.
Zemel, Benjamin M, "Novel Modulation of a Dorsal Root Ganglion Potassium Channel by Calcineurin and Protein Kinase C" (2017). ETD Collection for Thomas Jefferson University. AAI10616472.