Nomenclature: TSH receptor

Family: Glycoprotein hormone receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates. 

Contents

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 764 14q31 TSHR thyroid stimulating hormone receptor 27,30
Mouse 7 764 12 D3 Tshr thyroid stimulating hormone receptor 47
Rat 7 764 6q31 Tshr thyroid stimulating hormone receptor 1
Previous and Unofficial Names
Thyroid-Stimulating Hormone Receptor
Thyrotropin Receptor
LGR3
TSHRA
TSH-R
Thyroid stimulating hormone receptor
thyroid stimulating hormone, receptor
hyt
pet
hypothroid
AI481368
Database Links
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
GPCRDB
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
Orphanet Gene
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Natural/Endogenous Ligands
TSH {Sp: Human} , TSH {Sp: Mouse} , TSH {Sp: Rat}
Agonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Affinity Units Reference
TSH {Sp: Human} Hs Agonist - -
Agonist Comments
The TSH receptor is the primary target for the approved drug thyrotropin alfa, a recombinant form of the endogenous peptide.

Human TSH (thyrotropin) displays much lower binding affinity and lower potency than bovine TSH [38] on the human and other mammalian TSH receptors, making it impossible to measure Kd. This may be correlated to the evolutionary appearance of hCG in primates [49].

Murine [4,8-9,45] and human [44] stimulating monoclonal antibodies and human thyrostimulin [31] are also TSH receptor agonists.
Antagonist Comments
Murine blocking monoclonal antibodies are TSH receptor antagonists [8,43].
Primary Transduction Mechanisms
Transducer Effector/Response
Gs family Adenylate cyclase stimulation
Comments:  In the human species, stimulation of the Gs regulatory cascade positively controls the function (secretion of thyroid hormones) and the growth of thyrocytes. Continuous basal stimulation of this cascade is required to maintain the differentiation state of the thyroid gland.
References:  3
Secondary Transduction Mechanisms
Transducer Effector/Response
Gq/G11 family Phospholipase C stimulation
Comments:  Stimulation of the Gq cascade is associated in the human species with H2O2 production, which is required for activation of thyroid hormone synthesis.
References:  3
Tissue Distribution
Thyroid gland.
Species:  Human
Technique:  Northern blotting.
References:  27,30
Brain (neuronal cells and astrocyte): Areas include hippocampus, piriform, postcingulate cortex, hypothalamic nuclei, choroid plexus, cerebellum.
Species:  Rat
Technique:  in situ hybridisation.
References:  10
Tissue Distribution Comments
The major site of expression for the TSH receptor is the thyroid gland [27,30]. Receptor transcripts found in extrathyroid tissues have, at present, undefined function [56].
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
Measurement of cAMP levels in CHO cells transfected with the human TSH receptor.
Species:  Rat
Tissue:  CHO cells.
Response measured:  Stimulation of cAMP accumulation.
References:  35
Measurement of cAMP levels in the thyroid cell line FRTL5 following stimulation by thryrotropin or autoantibodies.
Species:  Rat
Tissue:  Thyroid cell line FRTL5.
Response measured:  Stimulation of cAMP accumulation.
References:  55
Physiological Functions
Stimulation of thyroid hormone production.
Species:  Mouse
Tissue:  In vivo.
References:  28
Stimulation of thyroid growth.
Species:  Mouse
Tissue:  Thyroid gland.
References:  37
Maintainence of thyroid cell differentiation.
Species:  Mouse
Tissue:  Thyroid gland.
References:  37
Physiological Consequences of Altering Gene Expression
TSH receptor knockout mice exhibit normal thyroid development at birth, but profound hypothyroidism. Bone anomalies have been reported but their relation with a function with a function of the TSH receptor in bone remains controversial.
Species:  Human
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  28
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Tshrhyt Tshrhyt/Tshrhyt
CBy.RF-Tshr/J
MGI:98849  MP:0004738 abnormal brainstem auditory evoked potential PMID: 16780814 
Tshrhyt Tshrhyt/Tshrhyt
CBy.RF-Tshr/J
MGI:98849  MP:0004736 abnormal distortion product otoacoustic emission PMID: 10575115 
Tshrhyt Tshrhyt/Tshrhyt
CBy.RF-Tshr/J
MGI:98849  MP:0003243 abnormal dopaminergic neuron morphology PMID: 11530227 
Tshrhyt Tshrhyt/Tshrhyt
CBy.RF-Tshr/J
MGI:98849  MP:0003194 abnormal frequency of paradoxical sleep PMID: 11690529 
Tshrhyt Tshrhyt/Tshrhyt
CBy.RF-Tshr/J
MGI:98849  MP:0000042 abnormal organ of Corti PMID: 10575115 
Tshrhyt Tshrhyt/Tshrhyt
CBy.RF-Tshr/J
MGI:98849  MP:0004527 abnormal outer hair cell stereociliary bundle morphology PMID: 10575115 
Tshrhyt Tshrhyt/Tshrhyt
CBy.RF-Tshr/J
MGI:98849  MP:0003149 abnormal tectorial membrane morphology PMID: 10575115 
Tshrtm1Rmar Tshrtm1Rmar/Tshrtm1Rmar
involves: 129S1/Sv * C57BL/6J
MGI:98849  MP:0004696 abnormal thyroid follicle morphology PMID: 12432094 
Tshrhyt Tshrhyt/Tshrhyt
involves: BALB/cByJ * RF/J
MGI:98849  MP:0004696 abnormal thyroid follicle morphology PMID: 7209519 
Tshrtm1Rmar Tshrtm1Rmar/Tshrtm1Rmar
involves: 129S1/Sv * C57BL/6J
MGI:98849  MP:0005468 abnormal thyroid hormone level PMID: 12432094 
Tshrtm1Rmar Tshrtm1Rmar/Tshrtm1Rmar
involves: 129S1/Sv * C57BL/6J
MGI:98849  MP:0002876 abnormal thyroid physiology PMID: 12432094 
Tshrhyt Tshrhyt/Tshrhyt
CBy.RF-Tshr/J
MGI:98849  MP:0004014 abnormal uterine environment PMID: 11690529 
Tshrhyt Tshrhyt/Tshrhyt
CBy.RF-Tshr/J
MGI:98849  MP:0009009 absent estrous cycle PMID: 11690529 
Tshrhyt Tshrhyt/Tshrhyt
involves: BALB/cByJ * RF/J
MGI:98849  MP:0001577 anemia PMID: 7209519 
Tshrhyt Tshrhyt/Tshrhyt
CBy.RF-Tshr/J
MGI:98849  MP:0001394 circling PMID: 11530227 
Tshrhyt Tshrhyt/Tshrhyt
CBy.RF-Tshr/J
MGI:98849  MP:0001967 deafness PMID: 16780814 
Tshrtm1Rmar Tshrtm1Rmar/Tshrtm1Rmar
involves: 129S1/Sv * C57BL/6J
MGI:98849  MP:0003503 decreased activity of thyroid PMID: 12432094 
Tshrhyt Tshrhyt/Tshrhyt
CBy.RF-Tshr/J
MGI:98849  MP:0005017 decreased B cell number PMID: 10570273 
Tshrhyt Tshrhyt/Tshrhyt
CBy.RF-Tshr/J
MGI:98849  MP:0001258 decreased body length PMID: 11530227 
Tshrhyt Tshrhyt/Tshrhyt
CBy.RF-Tshr/J
MGI:98849  MP:0001265 decreased body size PMID: 11530227 
Tshrhyt Tshrhyt/Tshrhyt
involves: BALB/cByJ * RF/J
MGI:98849  MP:0001265 decreased body size PMID: 7209519 
Tshrhyt Tshrhyt/Tshrhyt
CBy.RF-Tshr/J
MGI:98849  MP:0001262 decreased body weight PMID: 11530227 
Tshrhyt Tshrhyt/Tshrhyt
CBy.RF-Tshr/J
MGI:98849  MP:0004765 decreased brainstem auditory evoked potential PMID: 10575115 
Tshrtm1Rmar Tshrtm1Rmar/Tshrtm1Rmar
involves: 129S1/Sv * C57BL/6J
MGI:98849  MP:0003351 decreased circulating levels of thyroid hormone PMID: 12432094 
Tshrhyt Tshrhyt/Tshrhyt
CBy.RF-Tshr/J
MGI:98849  MP:0005185 decreased circulating progesterone level PMID: 11690529 
Tshrtm1Rmar Tshrtm1Rmar/Tshrtm1Rmar
involves: 129S1/Sv * C57BL/6J
MGI:98849  MP:0005478 decreased circulating thyroxine level PMID: 12432094 
Tshrhyt Tshrhyt/Tshrhyt
involves: BALB/cByJ * RF/J
MGI:98849  MP:0005478 decreased circulating thyroxine level PMID: 7209519 
Tshrtm1Rmar Tshrtm1Rmar/Tshrtm1Rmar
involves: 129S1/Sv * C57BL/6J
MGI:98849  MP:0005479 decreased circulating triiodothyronine level PMID: 12432094 
Tshrhyt Tshrhyt/Tshrhyt
CBy.RF-Tshr/J
MGI:98849  MP:0004402 decreased cochlear outer hair cell number PMID: 10575115 
Tshrhyt Tshrhyt/Tshrhyt
CBy.RF-Tshr/J
MGI:98849  MP:0004529 decreased outer hair cell stereocilia number PMID: 10575115 
Tshrhyt Tshrhyt/Tshrhyt
CBy.RF-Tshr/J
MGI:98849  MP:0003355 decreased ovulation rate PMID: 11690529 
Tshrhyt Tshrhyt/Tshrhyt
involves: BALB/cByJ * RF/J
MGI:98849  MP:0001926 female infertility PMID: 7209519 
Tshrhyt Tshrhyt/Tshrhyt
CBy.RF-Tshr/J
MGI:98849  MP:0003356 impaired luteinization PMID: 11690529 
Tshrhyt Tshrhyt/Tshrhyt
involves: BALB/cByJ * RF/J
MGI:98849  MP:0005178 increased circulating cholesterol level PMID: 7209519 
Tshrtm1Rmar Tshrtm1Rmar/Tshrtm1Rmar
involves: 129S1/Sv * C57BL/6J
MGI:98849  MP:0005122 increased circulating thyroid-stimulating hormone level PMID: 12432094 
Tshrhyt Tshrhyt/Tshrhyt
involves: BALB/cByJ * RF/J
MGI:98849  MP:0005122 increased circulating thyroid-stimulating hormone level PMID: 7209519 
Tshrhyt Tshrhyt/Tshrhyt
CBy.RF-Tshr/J
MGI:98849  MP:0008186 increased pro-B cell number PMID: 10570273 
Tshrhyt Tshrhyt/Tshrhyt
CBy.RF-Tshr/J
MGI:98849  MP:0001409 increased stereotypic behavior PMID: 11530227 
Tshrtm1Rmar Tshrtm1Rmar/Tshrtm1Rmar
involves: 129S1/Sv * C57BL/6J
MGI:98849  MP:0003501 iodide oxidation defect PMID: 12432094 
Tshrtm1Rmar Tshrtm1Rmar/Tshrtm1Rmar
involves: 129S1/Sv * C57BL/6J
MGI:98849  MP:0008569 lethality at weaning PMID: 12432094 
Tshrhyt Tshrhyt/Tshrhyt
involves: BALB/cByJ * RF/J
MGI:98849  MP:0001925 male infertility PMID: 7209519 
Tshrtm1Rmar Tshrtm1Rmar/Tshrtm1Rmar
involves: 129S1/Sv * C57BL/6J
MGI:98849  MP:0001732 postnatal growth retardation PMID: 12432094 
Tshrtm1Rmar Tshrtm1Rmar/Tshrtm1Rmar
involves: 129S1/Sv * C57BL/6J
MGI:98849  MP:0001921 reduced fertility PMID: 12432094 
Tshrtm1Rmar Tshrtm1Rmar/Tshrtm1Rmar
involves: 129S1/Sv * C57BL/6J
MGI:98849  MP:0002951 small thyroid gland PMID: 12432094 
Tshrhyt Tshrhyt/Tshrhyt
CBy.RF-Tshr/J
MGI:98849  MP:0001396 unidirectional circling PMID: 11530227 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Athyreosis
Orphanet:  95713
References:  32
Mutations not determined
Disease:  Familial gestational hyperthyroidism
OMIM:  603373
Orphanet:  99819
References: 
Mutations not determined
Disease:  Nonautoimmune hyperthyroidism
OMIM:  609152
Orphanet:  424
References: 
Mutations not determined
Disease:  Congenital nongoitrous hypothyroidism-1
OMIM:  275200
Orphanet:  90673
References: 
Mutations not determined
Disease:  Thyroid hypoplasia
Orphanet:  95720
References: 
Mutations not determined
Clinically-Relevant Mutations and Pathophysiology Comments
TSHR is also associated with the phenotypes of somatic, hyperfunctioning thyroid adenoma, and thyroid carcinoma with thyrotoxicosis. For more details see the OMIM entry linked to from the table of database links above.
Biologically Significant Variants
Type:  Single nucleotide polymorphisms.
Species:  Human
Description:  A number of activating single nucleotide polymorphisms have been identified in the human TSHR gene.

Extracellular domain:
Constitutively active: Ser281 -> Thr; Ser281 -> Asn; Ser281 -> Ile; Arg310 -> Cys.
Increased sensitivity to hCG: Lys183 -> Arg.
Reduced potency of TSH by ~20-fold: Cys390 -> Trp.

Transmembrane domain:
Constitutively active: Met453 -> Thr; Met463 -> Val; Ile486 -> Phe (IP pathway); Ile486 -> Met (PLC pathway); Val509 -> Ala; Leu512 -> Arg; Ile568 -> Thr; Val597 -> Leu; Val597 -> Phe; Tyr601 -> Asn; Asp619 -> Gly; Ala623 -> Val; Ala623 -> Ile; Ala623 -> Ser; Thr632 -> Ala; Phe631 -> Leu; Phe631 -> Ile; Asp633 -> Ala; Pro639 -> Ser; Val656 -> Phe; Cys672 -> Tyr; Leu677 -> Val; Met626 -> Ile (~13-fold higher);
Ligand-independent activation of the Gs AC system and the PLC pathway: Gly431 -> Ser.
Slightly increased affinity for bovine TSH: Ser505 -> Arg.
5-fold higher basal cAMP values than wild-type: Ser505 -> Asn.
3.5- to 4-fold higher basal cAMP values than wild-type: Leu629 -> Phe.
2-fold higher basal cAMP levels than wild-type: Asn650 -> Tyr.
References:  5,11-17,19-21,23-26,33-34,36,39-42,46,48,51,53-54
Type:  Single nucleotide polymorphisms.
Species:  Human
Description:  A number of inactivating single nucleotide polymorphisms have been identified in the human TSHR gene with a variety of consequences.

Extracellular domain:
Low expression and impaired signal transduction: Arg109 -> Gln.
2-fold increase in the potency of TSH: Pro162-> Ala.
Low expression at cell surface and reduced cAMP response to bovine TSH: Leu252 -> Pro.

Transmembrane domain:
Slightly decreased TSH binding: Arg450 -> His.
Poor cell-surface expression. Basal activity much lower than wild-type: Leu467 -> Pro.
TSH unresponsiveness in congenital hypothyroidism. Low cell-surface expression: Thr477 -> Ile.
Extremely low expression: Gly498 -> Ser.
Low expression:Trp546 -> X.
TSH unresponsiveness. Basal activity significantly lower than wild-type: Cys600 -> Arg.
No coupling to the IP pathway: Tyr601 -> His.
Low detectable basal activity and strongly reduced ability to activate AC in response to bovine TSH: Thr655 -> X.
References:  2,6-7,11,18,22,29,50,52
Available Assays
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PathHunter® U2OS TSHR(L) β-Arrestin-1 Cell Line (Cat no. 93-0912C3)
more info

REFERENCES

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To cite this database page, please use the following:

Sabine Costagliola, James A. Dias, Axel P.N. Themmen, Gilbert Vassart.
Glycoprotein hormone receptors: TSH receptor. Last modified on 25/03/2014. Accessed on 02/09/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=255.

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