A master thesis from Aalborg University
Molecular Mapping of the Binding Sites of a Nav1.1 Activator
[Molekylær Kortlægning af Bindingsstederne for en Nav1.1 Aktivator]
Author(s)
Term
4. term
Publication year
2018
Submitted on
2018-09-07
Pages
95 pages
Abstract
Schizophrenia constitutes one of the most complex psychiatric diseases whose environmental and genetic etiology make difficult to treat. The diverse pathologic targets implied, and an extreme genotypic variability in patients considerably reduce treatment efficacy. A continuous search for newer drugs is ongoing, as current pharmacological treatments fail to address broad cohorts of patients and, in the best of cases, only partly ameliorate the psychotic symptoms [1,2] . Latter research has set the focus on the role of interneurons in the regulation of neural networks and their significance in seizure episodes of several epilepsies [3,4] . The parvalbuminpositive (PV + ), GABAergic fast-spiking interneurons (FSINs) send inhibitory inputs to regulate the general excitatory output in a brain region [5,6] . Abundantly found on the axon initial segment (AIS) of these FSINs [7] , the voltage-gated sodium channel (VGSC) Nav1.1 has become an attractive target to use to potentiate their inhibitory effect over de-coordinated brain regions [8] . The newly discovered Nav1.1-specific Lundbeck modulator AA43279[9] binds to a yet-tobe discovered region in said channel. This project attempted to trace its exact mode of action by exchanging entire structural domains between VGSCs, and examining whether its effects vary along with the presence or absence of said channel subunits in the resulting whole chimeric constructs. But despite the majority of split Nav domains with tagged sfGFP were not functional, this strategy succeeded with simpler Kv2.1 monomers and may hold promising results when applied to other VGICs or LGICs, to allow their modification at a subunit-level and the analysis of their live functionalization in situ.
Keywords
Schizophrenia ; FSIN ; PV ; Nav1.1 ; Nav1.4 ; Kv2.1 ; chimera ; split ion channel ; sfGFP ; domain dimers ; modular approach
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