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    An examination of a sleep-related hypermotor epilepsy associated mutation in complex α4β2* nicotinic acetylcholine receptors

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    Smith_T_2022.pdf
    Embargo:
    2023-06-14
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    Author
    Smith, Tyler
    Chair
    Weltzin, Maegan
    Committee
    Kuhn, Thomas
    Drew, Kelly
    Dunlap, Kriya
    Keyword
    Epilepsy
    Frontal lobe epilepsy
    Nicotinic receptors
    Acetylcholine
    Metadata
    Show full item record
    URI
    http://hdl.handle.net/11122/13091
    Abstract
    Epilepsy is a disease that involves large networks of neurons. As such, studying the pathology of epilepsy has been complicated. Investigating epilepsy through the lens of Sleep-related Hypermotor Epilepsy (SHE) presents itself as a good strategy as SHE is linked to a variety of single point mutations. These mutations affect receptors, the most prominent being mutations in nicotinic acetylcholine receptors (nAChRs). nAChRs are pentameric ligand-gated ion channels. Five individual subunits combine to form a functional receptor. These nAChRs can either be homomeric, where all 5 subunits are the same, or heteromeric where there are different subunits combining. The most common CNS nAChRs are the homomeric [alpha] 7 nAChR and the heteromeric [alpha]4[beta]2 nAChR. Within these heteromeric nAChRs other subunits, such as the [alpha] 3 and [alpha] 5 subunits, can be incorporated into the accessory position. Many of the mutations in nAChRs linked to SHE are present in the transmembrane (TM) regions of the [alpha]4 and [beta]2 subunits of these [alpha]4[beta]2 nAChRs. However, less is known about the SHE mutations present in the intracellular loop regions. The [alpha]4[beta]2 subtype is widely distributed throughout the CNS. Our study looks at both [alpha]4[beta]2 isoforms as well as the more complex [alpha]4[beta]2)₂[alpha]3 and [alpha]4[beta]2)₂[alpha]5. The [alpha]3 and [alpha]5 accessory subunits are more highly expressed within the thalamocortical loop, the network implicated in SHE. Some prior research has been conducted on the [alpha]4[beta]2)₂[alpha]5 subtype and has shown that incorporation of the [alpha] 5 subunit increases the resulting receptor's Ca²⁺ permeability. Minimal work has been done on [alpha]4[beta]2)₂[alpha]3 subtype but research has shown that incorporating the [alpha]3 subunit into the [alpha]4[beta]2 nAChR results in low sensitivity to ACh and can be potentiated by compounds like NS-9283. We investigated the incorporation of the [alpha]4R³³⁶H SHE mutation into the [alpha]4[beta]2 isoforms as well as the ([alpha]4[beta]2)₂[alpha]3 and ([alpha]4[beta]2)₂[alpha]5 subtypes. Our results revealed that the [alpha]4R³³⁶H SHE mutation altered ACh pharmacology and overall receptor function. We also demonstrated that incorporation of the [alpha]3 or [alpha]5 subunits into the [alpha]4[beta]2 subtype caused changes in response to physiologically-relevant ligands. Our study adds to the knowledge of how the [alpha]4R³³⁶H SHE mutation contributes to changes in nAChR pharmacology and function. We also add to the growing knowledge of residues within the intracellular cytoplasmic loop region and their importance. Results from this study may be applicable to future studies involving generalized epilepsy, in which nAChRs are implicated. Study results could also be applicable to other neurological disorders such as Alzheimer's disease, Parkinson's disease, autism, and schizophrenia. These diseases, in many instances, involve alterations to various nAChR subtypes such as [alpha]7, [alpha]4[beta]2, [alpha]5 containing and [alpha]3-containing nAChRs.
    Description
    Thesis (M.S.) University of Alaska Fairbanks, 2022
    Date
    2022-08
    Type
    Thesis
    Collections
    Chemistry and Biochemistry

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