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Analysis of the interactions between GABAa receptor and L-triiodothyronine using electrophysiology and molecular dynamics simulations

Descriptive

Name (type = personal)
NamePart (type = family)
Westergard
NamePart (type = given)
Thomas
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Thomas Westergard
Role
RoleTerm (authority = RULIB)
author
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Martin
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Joseph
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Joseph Martin
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Advisory Committee
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chair
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Brannigan
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Grace
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Grace Brannigan
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Advisory Committee
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internal member
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McIlroy
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Patrick
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Patrick McIlroy
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Advisory Committee
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Rutgers University
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degree grantor
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Camden Graduate School
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school
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theses
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DateCreated (encoding = w3cdtf); (qualifier = exact)
2013
DateOther (encoding = w3cdtf); (qualifier = exact); (type = degree)
2013-05
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2013
Place
PlaceTerm (type = code)
xx
Language
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eng
Abstract (type = abstract)
Disorders of the thyroid cause a multitude of neurological dysfunctions including depression, anxiety, and psychosis. Thyroid hormones have been primarily thought to act via genomic mechanisms throughout the organism; however, another mechanism has been proposed for the adult brain. Functional experiments on expressed recombinant GABAA receptors demonstrated a rapid inhibition of GABA responses in the presence of the thyroid hormone triiodothyronine (T3), and, at much higher concentrations of T3 alone, a direct stimulation of receptor activity. We hypothesize that T3 acts directly on GABAA receptors via a mechanism similar to that of neurosteroids. To determine this mechanism of T3, competition studies with T3 against molecules with known binding motifs (ivermectin) were investigated utilizing two-electrode voltage-clamp measurements of the α1β1γ2 GABAA receptor expressed in Xenopus oocytes. T3 inhibited ivermectin in a competitive manner, with a Schild plot slope of 1.27 ± 0.03 and no significant difference from unity. All atom molecular dynamics were employed to analyze the possible interaction of T3 and the GABAA receptor (based on the crystal structure of the related glutamate-gated chloride channel). In simulations, T3 stabilizes in the transmembrane domain of the GABAA receptor in a region that is associated with the activation by neurosteroids. Our results provide strong evidence supporting earlier experimental findings indicating a role of T3 in regulating the activity of GABAA receptors in brain.
Subject (authority = RUETD)
Topic
Computational and Integrative Biology
Subject (authority = ETD-LCSH)
Topic
GABA--Receptors
Subject (authority = ETD-LCSH)
Topic
Thyroid gland--Diseases
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Rutgers University Electronic Theses and Dissertations
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ETD
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electronic resource
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application/pdf
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text/xml
Extent
1 online resource (vii, 36 p. : ill.)
Note (type = degree)
M.S.
Note (type = bibliography)
Includes bibliographical references
Note (type = statement of responsibility)
by Thomas Westergard
TitleInfo
Title
Analysis of the interactions between GABAa receptor and L-triiodothyronine using electrophysiology and molecular dynamics simulations
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Title
Camden Graduate School Electronic Theses and Dissertations
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rucore10005600001
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NjNbRU
Identifier (type = doi)
doi:10.7282/T36M3B0F
Genre (authority = ExL-Esploro)
ETD graduate
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Rights

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The author owns the copyright to this work.
RightsHolder (type = personal)
Name
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Westergard
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Thomas
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Permission or license
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2013-05
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Thomas Westergard
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Rutgers University. Camden Graduate School
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Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
Copyright
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Copyright protected
Availability
Status
Open
Reason
Permission or license
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2017-05-04T11:43:07
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2017-05-04T11:43:07
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