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TSH
| Previous and Unofficial Names |
| Thyroid-Stimulating Hormone Receptor |
| Thyrotropin Receptor |
| Structural Information |
|
class A G protein-coupled receptor |
| Species |
TM |
AA |
Chromosomal Location |
Gene Name |
Reference |
| Human |
7 |
764 |
14q31 |
TSHR
|
63-64 |
| Rat |
7 |
764 |
6q31 |
Tshr
|
62 |
| Mouse |
7 |
764 |
12 D3 |
Tshr
|
65 |
|
|
| Database Links |
|
ChEMBL Target |
78 (Hs) |
|
Ensembl |
ENSG00000165409 (Hs), ENSMUSG00000020963 (Mm), ENSRNOG00000003972 (Rn) |
|
Entrez Gene |
7253 (Hs), 22095 (Mm), 25360 (Rn) |
|
GeneCards |
TSHR (Hs) |
|
HomoloGene |
315 (Hs) |
|
OMIM |
603372 (Hs) |
|
PharmGKB Gene |
PA37042 (Hs) |
|
Protein Ontology (PRO) |
PRO:000001677 (Hs) |
|
RefSeq Nucleotide |
NM_000369 (Hs), NM_011648 (Mm), NM_012888 (Rn) |
|
RefSeq Protein |
NP_000360 (Hs), NP_035778 (Mm), NP_037020 (Rn) |
|
UniGene Hs. |
160411 (Hs) |
|
UniProt |
P16473 (Hs), P47750 (Mm), P21463 (Rn) |
|
Wikipedia |
TSH |
| Search for 3D structures on the PDB |
|
Search using keywords: Glycoprotein hormone receptors TSH
|
Search using accession numbers: P21463 || P16473 || P47750
|
| Agonist Comments |
| Human TSH (thyrotropin) displays much lower binding affinity and lower potency than bovine TSH [66] 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 [67].
Murine [68-71]and human [72] stimulating monoclonal antibodies and human thyrostimulin [73] are also TSH receptor agonists. |
| Antagonist Comments |
| Murine blocking monoclonal antibodies are TSH receptor antagonists [68,74]. |
| Primary Transduction Mechanisms
|
| Transducer |
Effector/Response |
|
Gs family |
Adenylate cyclase stimulation |
| Secondary Transduction Mechanisms |
| Transducer |
Effector/Response |
|
Gq/G11 family |
Phospholipase C stimulation |
| Tissue Distribution
|
| Thyroid gland. |
| Species: |
Human |
| Technique: |
Northern blotting. |
| References: |
63-64 |
|
|
| Brain (neuronal cells and astrocyte): Areas include hippocampus, piriform, postcingulate cortex, hypothalamic nuclei, choroid plexus, cerebellum. |
| Species: |
Rat |
| Technique: |
in situ hybridisation. |
| References: |
115 |
|
|
| Tissue Distribution Comments |
| The major site of expression for the TSH receptor is the thyroid gland [63-64]. Receptor transcripts found in extrathyroid tissues have, at present, undefined function [75]. |
| Functional Assays
|
| 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: |
113 |
|
|
| 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: |
114 |
|
|
| Physiological Functions
|
| Stimulation of thyroid hormone production. |
| Species: |
Mouse |
| Tissue: |
In vivo. |
| References: |
77 |
|
|
| Stimulation of thyroid growth. |
| Species: |
Mouse |
| Tissue: |
Thyroid gland. |
| References: |
116 |
|
|
| Maintainence of thyroid cell differentiation. |
| Species: |
Mouse |
| Tissue: |
Thyroid gland. |
| References: |
116 |
|
|
| 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 cntroversial. |
| Species: |
Human |
| Tissue: |
|
| Technique: |
Gene targeting in embryonic stem cells. |
| References: |
77 |
|
|
| Biologically Significant Variants
|
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. |
| Type: |
Single nucleotide polymorphisms. |
| Species: |
Human |
| References: |
78-104 |
|
|
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. |
| Type: |
Single nucleotide polymorphisms. |
| Species: |
Human |
| References: |
86,105-112 |
|
|
To cite this receptor data page, please use the following:
Sabine Costagliola, James A. Dias, Axel P.N. Themmen, Gilbert Vassart.
Glycoprotein hormone receptors: TSH. Last modified on 2010-06-30. Accessed on 2010-09-09. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=255.
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