Date of Award

2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Neuroscience

First Advisor

Steven S. Scherer

Abstract

The Kv7 (KCNQ) channel is a family of voltage-gated potassium channels that is considered to be important in the regulation of cellular excitability and axonal conduction. Previous studies have shown that peripheral sensory neurons express Kv7.2, Kv7.3, and Kv7.5 subunits, and that suppression of Kv7 activity with pharmacological blockers can lead to increased nociception. However, the specific localization and the functional role of each Kv7 subunits within the peripheral sensory system have not been fully elucidated. In this thesis, I first investigate the expression pattern of Kv7.5 with immunohistochemical techniques, which allow me to show that Kv7.5 is localized in the axons of the Remak bundles (unmyelinated axons and their associated Schwann cells), including their cutaneous branches, and is not detected at nodes of Ranvier. In addition, I demonstrate that small diameter neurons in the dorsal root ganglia (DRG), which are the origin of these unmyelinated afferents, express relatively more Kv7.5 than do large DRG neurons. Thus, Kv7.5 may be the relevant Kv7 channel expressed by C-fibers. Next I examined Kv7.2 with the generation of conditional Kcnq2-null mice that lacked Kv7.2 expression in all peripheral sensory neurons. I show that Kcnq2-null mice have a complete loss of Kv7.2 expression in the peripheral sensory neurons, but retain normal Kv7.3 nodal expression and other molecular components of the node, paranode, and juxtaparanode. Furthermore, the Kcnq2-null mice exhibit normal motor performance, but have increased thermal hyperalgesia and mechanical allodynia. Finally, by utilizing whole cell patch recording technique, I demonstrate that Kcnq2-null DRG neurons have increased excitability and reduced spike-frequency adaptation. Taken together, the results that I have generated in this thesis suggest that in the peripheral sensory system, Kv7.5 provides the primary M-current in unmyelinated axons, while Kv7.2 regulates the excitability of myelinated axon.

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