The role of thyrostimulin and its potential clinical significance

Karponis, Dimitrios; Ananth, Sachin

doi:10.1515/enr-2017-0012

Cited by 14 publications

(10 citation statements)

References 56 publications

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“…This suggests an increased metabolic rate in GHSR-KO mice, as even a onedegree increase in body temperature could thermodynamically correspond with a ten-percent rise in metabolic rate [30]. Thus, in a similar way to other hormones in animals, ghrelin may play a role in metabolism regulation, resulting in energy expenditure decrease through decreased thermogenesis [31]. However, the mice in this study were of global GHSR-knockout and is thus of limited specificity.…”

Section: Ghrelin and Adipositymentioning

confidence: 79%

The Physiological Role of Ghrelin in the Regulation of Energy and Glucose Homeostasis

Sovetkina¹,

Nadir²,

Fung³

et al. 2020

Cureus

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Ghrelin is a peptide hormone that is primarily released from the stomach. It is best known for its role in appetite initiation. However, evidence also suggests that ghrelin may play a much wider role in energy homeostasis and glucose metabolism. It is known that exogenous ghrelin exerts an orexigenic signal via growth hormone secretagogue receptors in the arcuate nucleus of the hypothalamus. However, blocking ghrelin signalling in the arcuate nucleus does not decrease feeding. Evidence now proposes that an alternative pathway for ghrelin's action is via the vagus nerve. Furthermore, it has been suggested that ghrelin signalling is an important physiological regulator of body adiposity and energy storage. Ghrelin also seems to be important in controlling glucose metabolism through action in the pancreatic islets of Langerhans, representing a promising novel therapeutic target in diabetes treatment. Despite these findings, further research in humans is required before ghrelin can be indicated as a therapeutic target in obesity or diabetes. This review summarises the current literature concerning ghrelin's physiological roles in energy and glucose homeostasis.

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Section: Ghrelin and Adipositymentioning

confidence: 79%

The Physiological Role of Ghrelin in the Regulation of Energy and Glucose Homeostasis

Sovetkina¹,

Nadir²,

Fung³

et al. 2020

Cureus

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“…The mechanism of action and physiological consequences of thyrostimulin remain largely unknown, and because a de facto thyrostimulin has yet to be extracted from blood or tissue, recombinant proteins have been used to characterize all binding, reporter, and in vivo / in vitro studies [5, 6, 10, 42, 54]. A wide range of potential physiological functions have been implicated for thyrostimulin, including cancer, immunity, and reproduction (reviewed in [60]). While thyrostimulin is hypothesized to be one of two pituitary GpHs in sea lamprey that function in an endocrine manner [11, 12, 47], there is no apparent conserved endocrine role in the elephant shark or mammals [6, 10].…”

Section: Discussionmentioning

confidence: 99%

Synteny and phylogenetic analysis of paralogous thyrostimulin beta subunits (GpB5) in vertebrates

Hausken

Levavi‐Sivan

2019

PLoS ONE

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At some point early in the vertebrate lineage, two whole genome duplication events (1R, 2R) took place that allowed for the diversification and sub-/neo-functionalization of the glycoprotein hormones (GpHs). All jawed vertebrates possess the GpHs luteinizing hormone (LH), follicle stimulating hormone (FSH), and thyroid stimulating hormone (TSH), each of which are heterodimers with a common alpha subunit and unique beta subunits. In 2002, a novel glycoprotein hormone named thyrostimulin was described to have unique GpA2 and GpB5 subunits that were homologous to the vertebrate alpha and beta subunits. The presence of GpA2 and GpB5 in representative protostomes and deuterostomes indicates their ancestry in the GpH family. There are several reports of GpH subunit evolution, but none have included GpA2 and GpB5 for species in each major vertebrate class. Thus, we addressed the ancestry of two paralogous GpB5 subunits (GpB5a and GpB5b) that were previously only recognized in two teleost species. Our search for orthologous GpB5a and GpB5b sequences in representative vertebrates and phylogenetic analysis, in addition to the currently published evolutionary scenarios of the GpH family, supports that GpB5a and GpB5b are paralogs that arose from the first vertebrate whole genome duplication event (1R). Syntenic analysis supports lineage specific losses of GpB5a in chondrichthyes, basal actinopterygians, and tetrapods, and retention in coelacanth and teleosts. Additionally, we were unable to identify GpA2 transcripts from tilapia mRNA, suggesting that this species does not produce heterodimeric thyrostimulin. While the conserved or even species-specific functional role of thyrostimulin or its individual subunits are still unknown in vertebrates, the analyses presented here provide context for future studies on the functional divergence of the GpH family.

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“…Indeed, we previously showed that TSHR couples to G q to activate phospholipase C to stimulate inositol-1,4,5-trisphosphate production with a 100-fold lower potency (EC 50 ) for TSH compared with G s activation (Allen et al, 2011). We found that activation of HEK 293 cells stably expressing the TSHR (HEK-TSHR cells) with TSH and thyrostimulin (a second TSHR cognate ligand) (Nakabayashi et al, 2002;Karponis and Ananth, 2017) exhibits IUDRC regulation of cAMP production. We show that this biphasic regulation occurs via activation of G s at low doses and by G i/ G o at high doses of TSHR ligands.…”

Section: Introductionmentioning

confidence: 99%

Thyrotropin Causes Dose-dependent Biphasic Regulation of cAMP Production Mediated by G_sand G_i/oProteins

et al. 2019

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The thyrotropin (TSH) receptor (TSHR) signals via G proteins of all four classes and b-arrestin 1. Stimulation of TSHR leads to increasing cAMP production that has been reported as a monotonic dose-response curve that plateaus at high TSH doses. In HEK 293 cells overexpressing TSHRs (HEK-TSHR cells), we found that TSHR activation exhibits an "inverted U-shaped dose-response curve" with increasing cAMP production at low doses of TSH and decreased cAMP production at high doses (.1 mU/ml). Since protein kinase A inhibition by H-89 and knockdown of b-arrestin 1 or b-arrestin 2 did not affect the decreased cAMP production at high TSH doses, we studied the roles of TSHR downregulation and of G i /G o proteins. A high TSH dose (100 mU/ml) caused a 33% decrease in cell-surface TSHR. However, because inhibiting TSHR downregulation with combined expression of a dominant negative dynamin 1 and b-arrestin 2 knockdown had no effect, we concluded that downregulation is not involved in the biphasic cAMP response. Pertussis toxin, which inhibits activation of G i /G o , abolished the biphasic response with no statistically significant difference in cAMP levels at 1 and 100 mU/ml TSH. Concordantly, coknockdown of G i /G o proteins increased cAMP levels stimulated by 100 mU/ml TSH from 55% to 73% of the peak level. These data show that biphasic regulation of cAMP production is mediated by G s and G i /G o at low and high TSH doses, respectively, which may represent a mechanism to prevent overstimulation in TSHR-expressing cells. SIGNIFICANCE STATEMENT We demonstrate biphasic regulation of TSH-mediated cAMP production involving coupling of the TSH receptor (TSHR) to Gs at low TSH doses and to G i/o at high TSH doses. We suggest that this biphasic cAMP response allows the TSHR to mediate responses at lower levels of TSH and that decreased cAMP production at high doses may represent a mechanism to prevent overstimulation of TSHR-expressing cells. This mechanism could prevent chronic stimulation of thyroid gland function.

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The role of thyrostimulin and its potential clinical significance

Cited by 14 publications

References 56 publications

The Physiological Role of Ghrelin in the Regulation of Energy and Glucose Homeostasis

The Physiological Role of Ghrelin in the Regulation of Energy and Glucose Homeostasis

Synteny and phylogenetic analysis of paralogous thyrostimulin beta subunits (GpB5) in vertebrates

Thyrotropin Causes Dose-dependent Biphasic Regulation of cAMP Production Mediated by G_sand G_i/oProteins

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The role of thyrostimulin and its potential clinical significance

Cited by 14 publications

References 56 publications

The Physiological Role of Ghrelin in the Regulation of Energy and Glucose Homeostasis

The Physiological Role of Ghrelin in the Regulation of Energy and Glucose Homeostasis

Synteny and phylogenetic analysis of paralogous thyrostimulin beta subunits (GpB5) in vertebrates

Thyrotropin Causes Dose-dependent Biphasic Regulation of cAMP Production Mediated by Gsand Gi/oProteins

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Thyrotropin Causes Dose-dependent Biphasic Regulation of cAMP Production Mediated by G_sand G_i/oProteins