Thyroid-Stimulating Hormone and Thyroid-Stimulating Hormone Receptor Structure-Function Relationships

This review focuses on recent advances in the structure-function relationships of thyroid-stimulating hormone (TSH) and its receptor. TSH is a member of the glycoprotein hormone family constituting a subset of the cystine-knot growth factor superfamily. TSH is produced by the pituitary thyrotrophs and released to the circulation in a pulsatile manner. It stimulates thyroid functions using specific membrane TSH receptor (TSHR) that belongs to the superfamily of G protein-coupled receptors (GPCRs). New insights into the structure-function relationships of TSH permitted better understanding of the role of specific protein and carbohydrate domains in the synthesis, bioactivity, and clearance of this hormone. Recent progress in studies on TSHR as well as studies on the other GPCRs provided new clues regarding the molecular mechanisms of receptor activation. Such advances are a result of extensive site-directed mutagenesis, peptide and antibody approaches, detailed sequence analyses, and molecular modeling as well as studies on naturally occurring gain- and loss-of-function mutations. This review integrates expanding information on TSH and TSHR structure-function relationships and summarizes current concepts on ligand-dependent and -independent TSHR activation. Special emphasis has been placed on TSH domains involved in receptor recognition, constitutive activity of TSHR, new insights into the evolution of TSH bioactivity, and the development of high-affinity TSH analogs. Such structural, physiological, pathophysiological, evolutionary, and therapeutic implications of TSH-TSHR structure-function studies are frequently discussed in relation to concomitant progress made in studies on gonadotropins and their receptors.

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Advances in the Regulation of Mammalian Follicle-Stimulating Hormone Secretion

Animals ◽

10.3390/ani11041134 ◽

2021 ◽

Vol 11 (4) ◽

pp. 1134

Author(s):

Hao-Qi Wang ◽

Wei-Di Zhang ◽

Bao Yuan ◽

Jia-Bao Zhang

Keyword(s):

Molecular Mechanisms ◽

Current Knowledge ◽

Follicle Stimulating Hormone ◽

Hormone Secretion ◽

Β Subunit ◽

Glycoprotein Hormone ◽

Livestock Breeding ◽

Biological Specificity ◽

Therapeutic Development ◽

Stimulating Hormone

Mammalian reproduction is mainly driven and regulated by the hypothalamic-pituitary-gonadal (HPG) axis. Follicle-stimulating hormone (FSH), which is synthesized and secreted by the anterior pituitary gland, is a key regulator that ultimately affects animal fertility. As a dimeric glycoprotein hormone, the biological specificity of FSH is mainly determined by the β subunit. As research techniques are being continuously innovated, studies are exploring the underlying molecular mechanism regulating the secretion of mammalian FSH. This article will review the current knowledge on the molecular mechanisms and signaling pathways systematically regulating FSH synthesis and will present the latest hypothesis about the nuclear cross-talk among the various endocrine-induced pathways for transcriptional regulation of the FSH β subunit. This article will provide novel ideas and potential targets for the improved use of FSH in livestock breeding and therapeutic development.

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The Hinge Region of Human Thyroid-Stimulating Hormone (TSH) Receptor Operates as a Tunable Switch between Hormone Binding and Receptor Activation

PLoS ONE ◽

10.1371/journal.pone.0040291 ◽

2012 ◽

Vol 7 (7) ◽

pp. e40291 ◽

Cited By ~ 8

Author(s):

Ritankar Majumdar ◽

Rajan R. Dighe

Keyword(s):

Receptor Activation ◽

Thyroid Stimulating Hormone ◽

Hinge Region ◽

Tsh Receptor ◽

Human Thyroid ◽

Hormone Binding ◽

Stimulating Hormone

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Thyrostimulin, a heterodimer of two new human glycoprotein hormone subunits, activates the thyroid-stimulating hormone receptor

Journal of Clinical Investigation ◽

10.1172/jci0214340 ◽

2002 ◽

Vol 109 (11) ◽

pp. 1445-1452 ◽

Cited By ~ 114

Author(s):

Koji Nakabayashi ◽

Hirotaka Matsumi ◽

Alka Bhalla ◽

Jeehyeon Bae ◽

Sietse Mosselman ◽

...

Keyword(s):

Hormone Receptor ◽

Thyroid Stimulating Hormone ◽

Glycoprotein Hormone ◽

Stimulating Hormone

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A vital region for human glycoprotein hormone trafficking revealed by an LHB mutation

Journal of Endocrinology ◽

10.1530/joe-16-0384 ◽

2016 ◽

Vol 231 (3) ◽

pp. 197-207 ◽

Cited By ~ 21

Author(s):

Iulia Potorac ◽

Adolfo Rivero-Müller ◽

Ashutosh Trehan ◽

Michał Kiełbus ◽

Krzysztof Jozwiak ◽

...

Keyword(s):

Luteinizing Hormone ◽

Pubertal Development ◽

Gene Mutations ◽

Thyroid Stimulating Hormone ◽

Beta Subunits ◽

Glycoprotein Hormones ◽

Glycoprotein Hormone ◽

Pubertal Delay ◽

The Common ◽

Stimulating Hormone

Glycoprotein hormones are complex hormonally active macromolecules. Luteinizing hormone (LH) is essential for the postnatal development and maturation of the male gonad. Inactivating Luteinizing hormone beta (LHB) gene mutations are exceptionally rare and lead to hypogonadism that is particularly severe in males. We describe a family with selective LH deficiency and hypogonadism in two brothers. DNA sequencing of LHB was performed and the effects of genetic variants on hormone function and secretion were characterized by mutagenesis studies, confocal microscopy and functional assays. A 20-year-old male from a consanguineous family had pubertal delay, hypogonadism and undetectable LH. A homozygous c.118_120del (p.Lys40del) mutation was identified in the patient and his brother, who subsequently had the same phenotype. Treatment with hCG led to pubertal development, increased circulating testosterone and spermatogenesis. Experiments in HeLa cells revealed that the mutant LH is retained intracellularly and showed diffuse cytoplasmic distribution. The mutated LHB heterodimerizes with the common alpha-subunit and can activate its receptor. Deletion of flanking glutamic acid residues at positions 39 and 41 impair LH to a similar extent as deletion of Lys40. This region is functionally important across all heterodimeric glycoprotein hormones, because deletion of the corresponding residues in hCG, follicle-stimulating hormone and thyroid-stimulating hormone beta-subunits also led to intracellular hormone retention. This novel LHB mutation results in hypogonadism due to intracellular sequestration of the hormone and reveals a discrete region in the protein that is crucial for normal secretion of all human glycoprotein hormones.

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Functional analysis of the human concentrative nucleoside transporter-1 variant hCNT1S546P provides insight into the sodium-binding pocket

AJP Cell Physiology ◽

10.1152/ajpcell.00198.2011 ◽

2012 ◽

Vol 302 (1) ◽

pp. C257-C266 ◽

Cited By ~ 9

Author(s):

Pedro Cano-Soldado ◽

Edurne Gorraitz ◽

Ekaitz Errasti-Murugarren ◽

F. Javier Casado ◽

M. Pilar Lostao ◽

...

Keyword(s):

Molecular Mechanisms ◽

Binding Pocket ◽

Site Directed Mutagenesis ◽

Hill Coefficient ◽

Thymidine Uptake ◽

Nucleoside Transporter ◽

Nucleotide Polymorphisms ◽

Loss Of Function ◽

Serine Residue ◽

Concentrative Nucleoside Transporter

SLC28 genes, encoding concentrative nucleoside transporter proteins (CNT), show little genetic variability, although a few single nucleotide polymorphisms (SNPs) have been associated with marked functional disturbances. In particular, human CNT1S546P had been reported to result in negligible thymidine uptake. In this study we have characterized the molecular mechanisms responsible for this apparent loss of function. The hCNT1S546P variant showed an appropriate endoplasmic reticulum export and insertion into the plasma membrane, whereas loss of nucleoside translocation ability affected all tested nucleoside and nucleoside-derived drugs. Site-directed mutagenesis analysis revealed that it is the lack of the serine residue itself responsible for the loss of hCNT1 function. This serine residue is highly conserved, and mutation of the analogous serine in hCNT2 (Ser541) and hCNT3 (Ser568) resulted in total and partial loss of function, respectively. Moreover, hCNT3, the only member that shows a 2Na+/1 nucleoside stoichiometry, showed altered Na+ binding properties associated with a shift in the Hill coefficient, consistent with one Na+ binding site being affected by the mutation. Two-electrode voltage-clamp studies using the hCNT1S546P mutant revealed the occurrence of Na+ leak, which was dependent on the concentration of extracellular Na+ indicating that, although the variant is unable to transport nucleosides, there is an uncoupled sodium transport.

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OR16-05 Single-Cell Sequencing Identifies Novel Regulators of Thyrotrope Populations and POU1F1-Independent Thyroid-Stimulating Hormone Expression

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.655 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Leonard Cheung ◽

Alexandre Daly ◽

Michelle Brinkmeier ◽

Sally Ann Camper

Keyword(s):

Transcription Factor ◽

Single Cell ◽

Molecular Mechanisms ◽

Thyroid Stimulating Hormone ◽

Pars Tuberalis ◽

Pituitary Cells ◽

Pars Distalis ◽

Mouse Development ◽

Single Cell Sequencing ◽

Stimulating Hormone

Abstract We implemented single-cell RNA sequencing (scRNAseq) technology as a discovery tool to identify factors enriched in differentiated thyrotropes. Thyroid-stimulating hormone (TSH) is produced in the pars distalis of the anterior pituitary (AP) and primarily acts on the thyroid gland to regulate metabolism through T3/T4. However, TSH is also produced by cells in the pars tuberalis (PT), which is comprised of a thin layer of cells that extends rostrally from the pars distalis along the pituitary stalk to the median eminence in the hypothalamus. TSH produced by PT thyrotropes acts on hypothalamic tanycytes to regulate seasonal reproduction. PT thyrotropes likely descend from rostral tip thyrotropes that arise at e12.5 of mouse development, which transcribe the TSH beta subunit (Tshb) without detectable expression of the transcription factor POU1F1. POU1F1 is required for Tshb transcription in thyrotropes of the adenohypophysis, and it acts synergistically with GATA2 to drive cell fate. The molecular mechanisms driving Tshb expression independently of Pou1f1 in PT thyrotropes are unclear. Thyrotropes are the least abundant endocrine cell-type in the pituitary gland. We used genetic labeling and fluorescence-activated cell sorting (FACS) to enrich for thyrotropes for single-cell sequencing. We performed scRNAseq on 7-day-old GFP-positive pituitary cells from Tshb-Cre; R26-LSL-eYFP and intact whole pituitaries, recovering more than 15,000 cells altogether. We observe two distinct populations of cells expressing Tshb. The larger thyrotrope population has approximately twenty fold higher levels of Tshb and five fold higher Cga transcripts than the smaller population, and they are also distinguished by expression of Pou1f1, TSH-releasing hormone receptor (Trhr), and deiodinase 2 (Dio2), consistent with expectations for AP thyrotropes. The smaller thyrotrope population does not express Pou1f1, but those cells are characterized by expression of TSH receptor (Tshr) and melatonin receptor 1A (Mtnr1a), consistent with expectations for PT thyrotropes. They express mildly increased levels of Eya3 and Six1, although these genes are expressed in other cell-types including AP thyrotropes, stem cells, and gonadotropes. They have two-fold higher levels of Gata2 transcripts and uniquely express the transcription factor Sox14. SOX14 is a SoxB2 family transcription factor that counteracts the transcriptional activity of SoxB1 family members, such as Sox2. In conclusion, our scRNAseq has identified novel markers of PT thyrotropes and unveils novel insights into the similarities and differences in the development and function of pituitary thyrotrope subpopulations.

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Molecular regulation of follicle-stimulating hormone synthesis, secretion and action

Journal of Molecular Endocrinology ◽

10.1530/jme-17-0308 ◽

2018 ◽

Vol 60 (3) ◽

pp. R131-R155 ◽

Cited By ~ 14

Author(s):

Nandana Das ◽

T Rajendra Kumar

Keyword(s):

Molecular Mechanisms ◽

Follicle Stimulating Hormone ◽

Thyroid Stimulating Hormone ◽

Α Subunit ◽

Physiological Regulation ◽

Hormone Synthesis ◽

The Common ◽

Blocking Antibodies ◽

Recombinant Human Fsh ◽

Stimulating Hormone

Follicle-stimulating hormone (FSH) plays fundamental roles in male and female fertility. FSH is a heterodimeric glycoprotein expressed by gonadotrophs in the anterior pituitary. The hormone-specific FSHβ-subunit is non-covalently associated with the common α-subunit that is also present in the luteinizing hormone (LH), another gonadotrophic hormone secreted by gonadotrophs and thyroid-stimulating hormone (TSH) secreted by thyrotrophs. Several decades of research led to the purification, structural characterization and physiological regulation of FSH in a variety of species including humans. With the advent of molecular tools, availability of immortalized gonadotroph cell lines and genetically modified mouse models, our knowledge on molecular mechanisms of FSH regulation has tremendously expanded. Several key players that regulate FSH synthesis, sorting, secretion and action in gonads and extragonadal tissues have been identified in a physiological setting. Novel post-transcriptional and post-translational regulatory mechanisms have also been identified that provide additional layers of regulation mediating FSH homeostasis. Recombinant human FSH analogs hold promise for a variety of clinical applications, whereas blocking antibodies against FSH may prove efficacious for preventing age-dependent bone loss and adiposity. It is anticipated that several exciting new discoveries uncovering all aspects of FSH biology will soon be forthcoming.

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Novel Insights into the Molecular Mechanisms of Human Thyrotropin Action: Structural, Physiological, and Therapeutic Implications for the Glycoprotein Hormone Family

Endocrine Reviews ◽

10.1210/edrv.18.4.0305 ◽

1997 ◽

Vol 18 (4) ◽

pp. 476-501 ◽

Cited By ~ 58

Author(s):

Mathis Grossmann ◽

Bruce D. Weintraub ◽

Mariusz W. Szkudlinski

Keyword(s):

Molecular Mechanisms ◽

Glycoprotein Hormone ◽

Therapeutic Implications

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FSH in therapy: physiological basis, new preparations and clinical use

Reproductive Medicine Review ◽

10.1017/s0962279900001150 ◽

1995 ◽

Vol 4 (3) ◽

pp. 163-177 ◽

Cited By ~ 27

Author(s):

Manuela Simoni ◽

Eberhard Nieschlag

Keyword(s):

Follicle Stimulating Hormone ◽

Thyroid Stimulating Hormone ◽

Clinical Use ◽

Β Subunit ◽

Glycoprotein Hormone ◽

Physiological Basis ◽

Α Subunit ◽

And Function ◽

Polypeptide Chains ◽

Stimulating Hormone

Follicle stimulating hormone (FSH) is a glycoprotein hormone secreted by the pituitary gland that, together with luteinizing hormone (LH), controls development, maturation and function of the gonad. Like the related hormones, LH, thyroid stimulating hormone (TSH) and human chorionic gonadotropin (hCG), FSH consists of two polypeptide chains, α and β, bearing carbohydrate moietiesN-linked to asparagine (Asn) residues. The α subunit is common to all members of the glycoprotein hormone family, whereas the β subunit, although structurally very similar, differs in each hormone and confers specificity of action.

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