Sulentic Courtney (Committee Member), Goldstein David (Committee Member), Ladle David (Committee Member), Robert Fyffe (Advisor), Rich Mark (Committee Member)
Doctor of Philosophy (PhD)
The intrinsic membrane properties of neurons in the central nervous system are controlled by the tight regulation of membrane-bound ion channels. Rather than existing as static entities operating only in opened or closed states in fixed locations, ion channels are dynamic molecules with the capacity to adopt multiple functional states through conformational changes and/or post-translational modification - enabling flexibility in their activity. Furthermore, the location of ion channels within certain membrane compartments and/or signaling ensembles is critical to synaptic integration and shaping of firing properties, and can also be dynamically modified by changes in neuronal activity and pathology. In mammalian motoneurons, Kv2.1 channels, which underlie delayed rectifier potassium currents, form distinct clusters, and together with other components, are assembled into a highly regulated signaling ensemble. In the `typical' clustered state, these channels are phosphorylated, have slow gating kinetics and help maintain motoneuron repetitive firing. However, following pathological or prolonged excitatory drive, Kv2.1 channels are rapidly dephosphorylated by the protein phosphatase calcineurin, which has two consequences. First, Kv2.1 channels decluster and spread out in the membrane of soma and proximal dendrites. Secondly, the channels open earlier in the time course of the action potential and stay open longer and serve to homeostatically lower firing rate. Thus, Kv2 channels have the unique capacity to both increase or decrease neuronal excitability. Characterizing the dynamic changes of Kv2.1 in motoneurons will provide insights into the homeostatic regulation of firing rate through dynamic clustering and channel kinetics and will be key to interpreting pathophysiological changes in future studies.
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