G protein-coupled receptors (GPCRs) represent the largest family of signal-transducing molecules known. For example, GPCRs comprise more than 4% of the genes in Caenorhabditis elegans. GPCRs 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 GPCRs has been found in a growing number of human diseases and GPCRs have been estimated to be the targets of more than 30% of the drugs used in clinical medicine today. Thus, understanding how GPCRs function at the molecular level is an important goal of biological research. We have used receptors for thyrotropin-releasing hormone (TRH) (TRH-Rs) as model GPCRs to study their structure and function. During this year, we have studied several new aspects of TRH-R structure and function. We compared several aspects of the biology of the two mouse TRH receptor types 1 (mTRH-R1) and 2 (mTRH-R2), which are 50% identical at the amino acid level. We studied the different signaling pathways/G proteins that are activated by mTRH-R1 versus mTRH-R2. We also continued our study of a viral GPCR, Kaposi's sarcoma-associated herpesvirus GPCR, and began studies of the receptor for thyrotropin (thyroid-stimulating hormone, TSH). In another aspect of the project, we synthesized several novel TRH analogs in which the histidine residue was modified to conain bulky alkyl groups and studied their biological properties. These analogs provided new insights into the size of the binding pocket for TRH within TRH-R1. Lastly, we have been exploring differences in the binding of mTRH-R1 and mTRH-R2 for competitive, small organic molecule, inverse agonists. We have tentatively identified a new series of 1-(phenyl)isoquinoline carboxamide analogs that discriminate between mTRH-R1 and mTRH-R2.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Intramural Research (Z01)
Project #
1Z01DK011006-03
Application #
6983589
Study Section
(RHA)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2004
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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