Date of Award
Spring 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Cellular and Molecular Physiology
First Advisor
Waxman, Stephen
Abstract
The burden of pain is significant and current pain treatments are often ineffective. Opiate use has led to an epidemic, requiring alternative pain medications that are more effective and non-addictive. Voltage-gated sodium channel NaV1.7 is preferentially expressed in pain-sensing neurons. Mutations in NaV1.7 can cause disorders ranging from intense pain to complete painlessness in humans, suggesting that its inhibition could provide analgesia without CNS side-effects or addictive potential. Indeed, existing non-selective NaV channels blockers prevent pain, but their utility is limited due to serious side-effects caused by inhibition of NaV isoforms expressed in the heart and brain. Selective inhibition of NaV1.7 is an attractive therapeutic strategy that would avoid these side effects. However, ongoing efforts to develop molecular inhibitors of NaV1.7 channels at the cell membrane have not yet resulted in new therapies. We propose an alternative strategy for inhibition of NaV1.7 function; reducing the number of channels at the cell surface by modulating their trafficking to and from the cell membrane. Implementing this therapeutic strategy would require identifying mechanisms that mediate the trafficking of specific NaV channels in peripheral axons. Whether such specific mechanisms for regulated NaV channel trafficking exist is not known. Because NaV channels are principal determinants of neuronal excitability, and their function is dependent on their transport and deployment to the plasma membrane, I hypothesized that the trafficking of NaV channels may be mediated by dedicated mechanisms or regulated differentially from other axonal proteins with different functions, and that understanding such mechanisms might present new therapeutic targets. The experiments described in this dissertation illuminate multiple aspects of NaV channel trafficking: 1. The specificity of NaV channels transport to axons by anterograde trafficking, 2. The mechanisms and specificity of NaV channel endocytosis, recycling, and degradation, and 3. The specificity of regulation of NaV channel trafficking by inflammatory mediators. Throughout these studies, I compared the trafficking of two exemplary depolarizing and hyperpolarizing channels in nociceptors – NaV1.7 and the voltage-gated potassium channel KV7.2, respectively. The results show that, while NaV1.7 is transported together in the same vesicles with KV7.2 in both the anterograde and retrograde directions, the transport of these proteins is differentially regulated by pain-related stimuli; inflammation specifically upregulates the anterograde trafficking of NaV1.7 over KV7.2, which leads to increased NaV1.7 at the axonal surface and increased nociceptor activity. Together, these studies demonstrate that NaV1.7 trafficking is specifically regulated by painful stimuli according to a functional logic and could potentially be targeted therapeutically.
Recommended Citation
Higerd-Rusli, Grant Philip, "Specificity and Regulation of Sodium Channel Trafficking: Exploring a Novel Therapeutic Strategy for Pain" (2023). Yale Graduate School of Arts and Sciences Dissertations. 1070.
https://elischolar.library.yale.edu/gsas_dissertations/1070
