Seven transmembrane-spanning receptors (7TMRs or G protein-coupled receptors, GPCRs) represent the largest family of signal-transducing molecules known. For example, 7TMRs comprise more than 4% of the genes in Caenorhabditis elegans. 7TMRs convey signals for light and many extracellular regulatory molecules, such as, hormones, growth factors and neurotransmitters, that regulate every cell in the body. Dysregulation of 7TMRs has been found in a growing number of human diseases and 7TMRs have been estimated to be the targets of more than 30% of the drugs used in clinical medicine today. Thus, understanding how 7TMRs function at the molecular level is an important goal of biological research. We have used receptors for thyrotropin-releasing hormone (TRH) (TRH-Rs) and, more recently, for thyroid-stimulating hormone (TSH-R) as model 7TMRs to study their structure and function. During this year, we have studied several new aspects of TRH-R structure and function. Using mutagenesis and molecular modeling approaches, we gained insight into how inverse agonists act in 7TMRs and how conformational changes lead to activation of 7TMRs. We identified a new series of 1-(phenyl)isoquinoline carboxamide analogs that are the first ligands that discriminate between the two subtypes of TRH-Rs, mTRH-R1 and mTRH-R2. We determined the importance of the post-translational modification of palmitoylation in TRH-R signaling. Lastly, we have begun to discover, design and synthesize low molecular weight ligands to probe TRH-R and TSH-R function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Intramural Research (Z01)
Project #
1Z01DK011006-04
Application #
7151493
Study Section
(RHA)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2005
Total Cost
Indirect Cost
Name
U.S. National Inst Diabetes/Digst/Kidney
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Neumann, Susanne; Eliseeva, Elena; Boutin, Alisa et al. (2018) Discovery of a Positive Allosteric Modulator of the Thyrotropin Receptor: Potentiation of Thyrotropin-Mediated Preosteoblast Differentiation In Vitro. J Pharmacol Exp Ther 364:38-45
Marcus-Samuels, Bernice; Krieger, Christine C; Boutin, Alisa et al. (2018) Evidence That Graves' Ophthalmopathy Immunoglobulins Do Not Directly Activate IGF-1 Receptors. Thyroid 28:650-655
Diana, Tanja; Daiber, Andreas; Oelze, Matthias et al. (2018) Stimulatory TSH-Receptor Antibodies and Oxidative Stress in Graves Disease. J Clin Endocrinol Metab 103:3668-3677
Krieger, Christine C; Perry, Joseph D; Morgan, Sarah J et al. (2017) TSH/IGF-1 Receptor Cross-Talk Rapidly Activates Extracellular Signal-Regulated Kinases in Multiple Cell Types. Endocrinology 158:3676-3683
Place, Robert F; Krieger, Christine C; Neumann, Susanne et al. (2017) Inhibiting thyrotropin/insulin-like growth factor 1 receptor crosstalk to treat Graves' ophthalmopathy: studies in orbital fibroblasts in vitro. Br J Pharmacol 174:328-340
Dougherty, John P; Wolff, Brian S; Cullen, Mary J et al. (2017) Taltirelin alleviates fatigue-like behavior in mouse models of cancer-related fatigue. Pharmacol Res 124:1-8
Krieger, Christine C; Place, Robert F; Bevilacqua, Carmine et al. (2016) TSH/IGF-1 Receptor Cross Talk in Graves' Ophthalmopathy Pathogenesis. J Clin Endocrinol Metab 101:2340-7
Morgan, Sarah J; Neumann, Susanne; Marcus-Samuels, Bernice et al. (2016) Thyrotropin and Insulin-Like Growth Factor 1 Receptor Crosstalk Upregulates Sodium-Iodide Symporter Expression in Primary Cultures of Human Thyrocytes. Thyroid 26:1794-1803
Boutin, Alisa; Neumann, Susanne; Gershengorn, Marvin C (2016) Multiple Transduction Pathways Mediate Thyrotropin Receptor Signaling in Preosteoblast-Like Cells. Endocrinology 157:2173-81
Dougherty, John P; Springer, Danielle A; Gershengorn, Marvin C (2016) The Treadmill Fatigue Test: A Simple, High-throughput Assay of Fatigue-like Behavior for the Mouse. J Vis Exp :

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