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Analysis of the interactions between GABAa receptor and L-triiodothyronine using electrophysiology and molecular dynamics simulations
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Westergard, Thomas. Analysis of the interactions between GABAa receptor and L-triiodothyronine using electrophysiology and molecular dynamics simulations. Retrieved from https://doi.org/doi:10.7282/T36M3B0F

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TitleAnalysis of the interactions between GABAa receptor and L-triiodothyronine using electrophysiology and molecular dynamics simulations
NameWestergard, Thomas (author); Martin, Joseph (chair); Brannigan, Grace (internal member); McIlroy, Patrick (internal member); Rutgers University; Camden Graduate School
Date Created2013
Other Date2013-05 (degree)
SubjectComputational and Integrative Biology, GABA--Receptors, Thyroid gland--Diseases
Extent1 online resource (vii, 36 p. : ill.)
DescriptionDisorders 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.
NoteM.S.
NoteIncludes bibliographical references
Noteby Thomas Westergard
Genretheses, ETD graduate
Persistent URLhttps://doi.org/doi:10.7282/T36M3B0F
Languageeng
CollectionCamden Graduate School Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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