A Gq Biased Small Molecule Active at the TSH Receptor

Autoimmune thyroid-stimulating antibodies are activating the thyrotropin receptor (TSHR) in both the thyroid and the eye, but different molecular mechanisms are induced in both organs, leading to Graves’ disease (GD) and Graves’ orbitopathy (GO), respectively. Therapy with anti-thyroid drugs to reduce hyperthyroidism (GD) by suppressing the biosynthesis of thyroid hormones has only an indirect effect on GO, since it does not causally address pathogenic TSHR activation itself. GO is thus very difficult to treat. The activated TSHR but also the cross-interacting insulin-like growth factor 1 receptor (IGF-1R) contribute to this issue. The TSHR is a heptahelical G-protein-coupled receptor, whereas the IGF-1R is a receptor tyrosine kinase. Despite these fundamental structural differences, both receptors are phosphorylated by G-protein receptor kinases, which enables β-arrestin binding. Arrestins mediate receptor internalization and also activate the mitogen-activated protein kinase pathway. Moreover, emerging results suggest that arrestin plays a critical role in the cross-interaction of the TSHR and the IGF-1R either in their common signaling pathway and/or during an indirect or potential TSHR/IGF-1R interaction. In this review, novel pharmacological strategies with allosteric small-molecule modulators to treat GO and GD on the level of the TSHR and/or the TSHR/IGF-1R cross-interaction will be discussed. Moreover, monoclonal antibody approaches targeting the TSHR or the IGF-1R and thereby preventing activation of either receptor will be presented. Another chapter addresses the immunomodulation to treat GO using TSHR-derived peptides targeting the human leukocyte antigen DR isotope (HLA-DR), which is a feasible approach to tackle GO, since HLA-DR and TSHR are overexpressed in orbital tissues of GO patients.

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“…5b) and was unable to activate cAMP production [77]. Moreover, a Gq-biased agonist, namely BSM1, was reported recently [78] (Fig. 1c).…”

Section: S37amentioning

confidence: 64%

“…Gαs is not activated. c BSM1[78] activates only Gαq and neither Gαs nor Gα 12-13 . d Extracellular bound TSH activates all 3 pathways.…”

mentioning

confidence: 99%

Modulating TSH Receptor Signaling for Therapeutic Benefit

Krause¹,

Eckstein²,

Schülein³

2020

Eur Thyroid J

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“…Activation of TSHR leads to dissociation of G proteins into the Ga and Gbg subunits which in turn trigger several canonical signal transduction cascades (112). TSHR can potentially couple to all four Ga protein families (Ga s , Ga q/11 , Ga i/o , and Ga 12/13 ) to activate several kinases that collectively regulate thyrocyte proliferation and TH synthesis and release (Figure 1) (113)(114)(115). The Ga s and Ga q/11 -induced signaling pathways are of the most importance in the thyrocytes.…”

Section: Tsh-stimulated Signal Transduction and Transcriptional Regul...mentioning

confidence: 99%

“…Like in many other types of cells (133)(134)(135)(136), there exist crosstalks between the cAMP/PKA and PLC/PKC pathway in thyrocytes. Elevated cAMP levels can inhibit PLC activity (137), and PLC/PKC in turn suppresses the cAMP/PKA pathway, despite that the mechanism of suppression remains to be identified (114). At high TSH concentrations, TSHR can also activate Ga i/o , which inhibits adenylate cyclase activity to decrease cAMP production (138,139).…”

Section: Tshr-activated Signal Transductionmentioning

confidence: 99%

“…PKC acts as a negative regulator of TH synthesis and secretion by inhibiting iodide organification ( 129 ). Preferential activation of the Gα q/11 /PKC pathway by using a specific small molecule also inhibited TSH-stimulated proliferation of FRTL-5 cells ( 114 ). For the stimulatory response mediated by Gq/PKC, cathepsin B activity and TH-generating TG degradation were increased after 1-2 h of TSH treatment ( 130 ).…”

Section: Tsh-stimulated Signal Transduction and Transcriptional Regul...mentioning

confidence: 99%

See 1 more Smart Citation

Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion

Zhang

2022

Front. Endocrinol.

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Thyroid hormones (THs), including T4 and T3, are produced and released by the thyroid gland under the stimulation of thyroid-stimulating hormone (TSH). The homeostasis of THs is regulated via the coordination of the hypothalamic-pituitarythyroid axis, plasma binding proteins, and local metabolism in tissues. TH synthesis and secretion in the thyrocytes-containing thyroid follicles are exquisitely regulated by an elaborate molecular network comprising enzymes, transporters, signal transduction machineries, and transcription factors. In this article, we synthesized the relevant literature, organized and dissected the complex intrathyroidal regulatory network into structures amenable to functional interpretation and systems-level modeling. Multiple intertwined feedforward and feedback motifs were identified and described, centering around the transcriptional and posttranslational regulations involved in TH synthesis and secretion, including those underpinning the Wolff-Chaikoff and Plummer effects and thyroglobulin-mediated feedback regulation. A more thorough characterization of the intrathyroidal network from a systems biology perspective, including its topology, constituent network motifs, and nonlinear quantitative properties, can help us to better understand and predict the thyroidal dynamics in response to physiological signals, therapeutic interventions, and environmental disruptions.

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Appreciating the potential for GPCR crosstalk with ion channels

Davies

Tomás

2023

Progress in Molecular Biology and Translational Science

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A Gq Biased Small Molecule Active at the TSH Receptor

Cited by 19 publications

References 52 publications

Modulating TSH Receptor Signaling for Therapeutic Benefit

Modulating TSH Receptor Signaling for Therapeutic Benefit

Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion

Appreciating the potential for GPCR crosstalk with ion channels

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