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Title: Post-transcriptional regulation and protein-protein interactions of the voltage-gated sodium channel Nav1.7
Author: Koenig, J.
ISNI:       0000 0004 8503 0785
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2015
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In mammals, ten isoforms of Nav channels (Nav1.1-1.9 and Nax) are known that exhibit specific spatial and temporal expression patterns. Human genetics and transgenic mouse studies have revealed a pivotal role for voltage-gated sodium channel Nav1.7 in both acute and chronic pain. Therefore Nav1.7 is a promising analgesic drug target as individuals with loss of function mutations are normal except for a complete inability to perceive pain and having anosmia. As Nav family members share high sequence homology, potential Nav1.7 blockers need to be highly selective. The aim of this thesis was to gain a greater understanding of Nav1.7. Firstly, I examined the regulation of the SCN9A gene, which encodes Nav1.7, through cloning and analysis of a natural antisense transcript (NAT). The complementary NAT overlaps tail-to-tail with the SCN9A/Scn9a sense transcript in both human and mouse genomes. Overexpression of the NAT in vitro specifically decreases the level of mRNA, protein and peak current of Nav1.7. Therefore the NAT may play an important role in regulating human pain thresholds and is a potential candidate gene for individuals with chronic pain disorders that map to the SCN9A locus. Secondly, I investigated the protein-interaction network of Nav1.7 through analysis of a newly developed Nav1.7 TAP tagged mouse. Here, I aimed to identify subtype specific interaction partners of Nav1.7 and found that Nav1.7 is associated with β3 and β4 subunits (Navβ) as well as functional molecules that play a crucial role in protein synthesis, intracellular trafficking and pain processing. Finally, I studied a newly developed mouse model of inherited Primary Erythromelalgia (PE, hNav1.7 L858F), a human pain disorder caused by a mutation in SCN9A. This hNav1.7 L858F TAP tag mouse line recapitulated the human PE phenotype and will potentially be useful in preclinical screening of candidate Nav1.7 blockers.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available