Seven transmembrane-spanning receptors (7TMRs or G protein-coupled receptors, GPCRs) represent the largest family of signal-transducing molecules known. 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 is an important goal of biological research. We have used receptors for thyrotropin-releasing hormone (TRH) (TRH-Rs) and for thyroid-stimulating hormone (TSH-R) as model 7TMRs to study their structure and function. During this year, we studied several new aspects of the structure and function of these receptors. 1) We used a novel small molecule agonist that we discovered to better understand the structure-function relationship and the signaling properties of the TSH-R. Specifically, we showed that although several mutant receptors that caused hypothyroidism in patients could not be activated by TSH, which binds to the large extracellular domain, but could be activated by a small molecule agonist, which binds to the transmembrane domain of TSH-R. This finding conclusively demonstrates the separate domains for binding and signaling. We also showed that these TSH-R mutants signal differently than the normal TSH-R. 2) We showed that the TRH-R signals persistently, that is, it continues to signal after the agonist TRH has been withdrawn. This is a new observation for TRH-R and for several other G protein-coupled receptors that explains how a transient exposure to an agonist can lead to a biologic response that lasts much longer.

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Morgan, Sarah J; Neumann, Susanne; Gershengorn, Marvin C (2018) Normal Human Thyrocytes in Culture. Methods Mol Biol 1817:1-7
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
Katz, Liora S; Xu, Shiliyang; Ge, Kai et al. (2018) T3 and Glucose Coordinately Stimulate ChREBP-Mediated Ucp1 Expression in Brown Adipocytes From Male Mice. Endocrinology 159:557-569
Citterio, Cintia E; Veluswamy, Balaji; Morgan, Sarah J et al. (2017) De novo triiodothyronine formation from thyrocytes activated by thyroid-stimulating hormone. J Biol Chem 292:15434-15444
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
Neumann, Susanne; Gershengorn, Marvin C (2017) Rebuttal to Smith and Janssen (Thyroid 2017;27:746-747. DOI: 10.1089/thy.2017.0281). Thyroid 27:1459-1460
Morgan, Sarah J; Neumann, Susanne; Marcus-Samuels, Bernice et al. (2016) Thyrotropin Stimulates Differentiation Not Proliferation of Normal Human Thyrocytes in Culture. Front Endocrinol (Lausanne) 7:168
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

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