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 showed that amino acid residues within the transmembrane helical bundle of TSH-R inhibited activation of the receptor. Based on our research into TSH-R, we were invited to contribute a review article on small molecule ligands of GPCRs. 2) It was recently reported that three GPCRs signal persistently when exposed to their cognate ligands and it was suggested that persistent signaling was dependent on receptor internalization. Because of the important implications of the conclusion that persistent GPCR signaling was dependent upon internalization, we studied this phenomenon. We showed that persistent cAMP signaling by TSH-R was not dependent on internalization. In a second study, we showed that TSH-R signals persistently via the inositol-1,4,5-trisphosphate-calcium pathway also. 3) We found a unique characteristic of TSH-R signaling via inositol-1,4,5-trisphosphate-calcium pathway that explains the important dose-response differences for cAMP and inositol-1,4,5-trisphosphate-calcium signaling. To signal via cAMP, TSH-R must bind a single molecule of TSH whereas to signal via inositol-1,4,5-trisphosphate-calcium it must bind 2 molecules of TSH , one to each protomer of the TSH-R dimer.

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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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