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.

Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2011
Total Cost
$1,234,873
Indirect Cost
City
State
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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
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
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
Boutin, Alisa; Neumann, Susanne; Gershengorn, Marvin C (2016) Multiple Transduction Pathways Mediate Thyrotropin Receptor Signaling in Preosteoblast-Like Cells. Endocrinology 157:2173-81
Krieger, Christine C; Neumann, Susanne; Place, Robert F et al. (2015) Bidirectional TSH and IGF-1 receptor cross talk mediates stimulation of hyaluronan secretion by Graves' disease immunoglobins. J Clin Endocrinol Metab 100:1071-7
Boutin, Alisa; Eliseeva, Elena; Gershengorn, Marvin C et al. (2014) ?-Arrestin-1 mediates thyrotropin-enhanced osteoblast differentiation. FASEB J 28:3446-55
Katz, Liora S; Geras-Raaka, Elizabeth; Gershengorn, Marvin C (2014) Heritability of fat accumulation in white adipocytes. Am J Physiol Endocrinol Metab 307:E335-44
Turcu, Adina F; Kumar, Seema; Neumann, Susanne et al. (2013) A small molecule antagonist inhibits thyrotropin receptor antibody-induced orbital fibroblast functions involved in the pathogenesis of Graves ophthalmopathy. J Clin Endocrinol Metab 98:2153-9

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