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
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
PhysicalDescription
Form (authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
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
RelatedItem (type = host)
TitleInfo
Title
Camden Graduate School Electronic Theses and Dissertations
Identifier (type = local)
rucore10005600001
Location
PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
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