TRH<sub>1</sub> receptor | Thyrotropin-releasing hormone receptors | IUPHAR/BPS Guide to PHARMACOLOGY

TRH1 receptor

Target id: 363

Nomenclature: TRH1 receptor

Family: Thyrotropin-releasing hormone receptors

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

   GtoImmuPdb view: OFF :     Currently no data for TRH1 receptor in GtoImmuPdb

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 398 8q23.1 TRHR thyrotropin releasing hormone receptor 8,17
Mouse 7 393 15 B3.2 Trhr thyrotropin releasing hormone receptor 22
Rat 7 412 7q31 Trhr thyrotropin releasing hormone receptor 6,29
Previous and Unofficial Names
TRH receptor | thyroliberin receptor | TRH-R | TRH-R1
Database Links
Specialist databases
GPCRDB trfr_human (Hs), trfr_mouse (Mm), trfr_rat (Rn)
Other databases
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands
TRH {Sp: Human, Mouse, Rat}

Download all structure-activity data for this target as a CSV file

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
[3H]MeTRH Rn Partial agonist 8.5 pKd 23
pKd 8.5 [23]
MeTRH Hs Partial agonist 8.5 pKi 26
pKi 8.5 [26]
TRH {Sp: Human, Mouse, Rat} Rn Full agonist 7.4 pKi 11
pKi 7.4 [11]
taltirelin Hs Full agonist 6.5 pKi 25
pKi 6.5 [25]
View species-specific agonist tables
Agonist Comments
It has been shown that in terms of efficacy (R)-desaza-TRH > NP-654 > (S)-desaza-TRH > TRH which is inversely related to their binding affinity values [9].
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
midazolam Rn Antagonist 5.5 pKi 7
pKi 5.5 (Ki 3.2x10-6 M) [7]
chlordiazepoxide Rn Antagonist 4.8 pKi 7
pKi 4.8 (Ki 1.5x10-5 M) [7]
chlordiazepoxide Mm Antagonist 4.7 pKi 22
pKi 4.7 (Ki 2x10-5 M) [22]
View species-specific antagonist tables
Antagonist Comments
Newer antagonists have been reported but are not readily available.
Primary Transduction Mechanisms
Transducer Effector/Response
Gq/G11 family Phospholipase C stimulation
References:  1,14
Tissue Distribution
Eye, brain and pituitary gland.
Species:  Mouse
Technique:  Quantitative PCR.
References:  21
Brain and pituitary gland.
Species:  Rat
Technique:  In situ hybridization.
References:  3,18,27
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 IP and Ca2+ levels in COS-1 cells transfected with the human TRH1 receptor.
Species:  Human
Tissue:  COS-1 cells.
Response measured:  Increased IP and Ca2+ levels.
References:  8
Measurement of PIP2 and IP levels in cells stimulated with TRH.
Species:  Rat
Tissue:  Cultured cells.
Response measured:  Stimulation of PIP2 degradation and IP formation.
References:  10,15
Measurement of PIP2 and IP levels in cells stimulated with TRH.
Species:  Mouse
Tissue:  Cultured cells.
Response measured:  Stimulation of PIP 2 degradation and IP formation.
References:  10,15
Physiological Functions
Stimulation of prolactin (PRL) release.
Species:  Human
Tissue:  In vivo.
References:  19
Stimulation of thyrotropin (TSH) release.
Species:  Human
Tissue:  In vivo.
References:  19
Stimulation of thyrotropin (TSH) release.
Species:  Rat
Tissue:  In vivo.
References:  19
TRH1 receptor, not TRH2 receptor primarily mediates taltirelin actions in the mouse CNS.
Species:  Mouse
Tissue:  CNS
References:  24
Physiological Functions Comments
Except for the pituitary receptors, the physiological function of TRH receptors in other areas remains undiscovered. The best data are from knockout mice where it has been shown that TRH1 is involved in depression and anxiety-like behaviours. TRH neurons as metabolic sensors to regulate the thyroid axis in response to physiologic demands [13]. Its effect on glucose homeostasis is controversial.
Physiological Consequences of Altering Gene Expression
TRH1 receptor knockout mice exhibit a slightly reduced growth rate, decreases in serum T3, T4 and prolactin levels but no alteration of thyroid-stimulating hormone levels, and increased depression and anxiety-like behavior.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  20,28
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Trhrtm1Bau Trhrtm1Bau/Trhrtm1Bau
involves: 129S1/Sv * 129X1/SvJ
MGI:98824  MP:0005121 decreased circulating prolactin level PMID: 14988432 
Trhrtm1Bau Trhrtm1Bau/Trhrtm1Bau
involves: 129S1/Sv * 129X1/SvJ
MGI:98824  MP:0005471 decreased thyroxine level PMID: 14988432 
Trhrtm1Bau Trhrtm1Bau/Trhrtm1Bau
involves: 129S1/Sv * 129X1/SvJ
MGI:98824  MP:0005473 decreased triiodothyronine level PMID: 14988432 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Resistance to thyrotropin-releasing hormone syndrome
Orphanet: ORPHA99832
References:  2,5
General Comments
Another TRH receptor, TRH2, has been cloned from the rat, mouse and several other species and shares approximately 50% homology with the TRH1 receptor [4,12,16,18]. A human form of the TRH2 receptor has not been found.

It had been thought that TRH2 was the primary mediator of the effects of TRH (and its analogs) in the central nervous system. This idea has recently been shown to be incorrect [24]. TRH1 is the primary mediator of the effects of TRH (and its analogs) in the central nervous system.

References

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1. Aragay AM, Katz A, Simon MI. (1992) The G alpha q and G alpha 11 proteins couple the thyrotropin-releasing hormone receptor to phospholipase C in GH3 rat pituitary cells. J Biol Chem, 267: 24983-24988. [PMID:1334076]

2. Bonomi M, Busnelli M, Beck-Peccoz P, Costanzo D, Antonica F, Dolci C, Pilotta A, Buzi F, Persani L. (2009) A family with complete resistance to thyrotropin-releasing hormone. N. Engl. J. Med., 360 (7): 731-4. [PMID:19213692]

3. Calzá L, Giardino L, Ceccatelli S, Zanni M, Elde R, Hökfelt T. (1992) Distribution of thyrotropin-releasing hormone receptor messenger RNA in the rat brain: an in situ hybridization study. Neuroscience, 51 (4): 891-909. [PMID:1488129]

4. Cao J, O'Donnell D, Vu H, Payza K, Pou C, Godbout C, Jakob A, Pelletier M, Lembo P, Ahmad S, Walker P. (1998) Cloning and characterization of a cDNA encoding a novel subtype of rat thyrotropin-releasing hormone receptor. J Biol Chem, 273: 32281-32287. [PMID:9822707]

5. Collu R, Tang J, Castagné J, Lagacé G, Masson N, Huot C, Deal C, Delvin E, Faccenda E, Eidne KA et al.. (1997) A novel mechanism for isolated central hypothyroidism: inactivating mutations in the thyrotropin-releasing hormone receptor gene. J. Clin. Endocrinol. Metab., 82 (5): 1561-5. [PMID:9141550]

6. de la Pena P, Delgado LM, del Camino D, Barros F. (1992) Cloning and expression of the thyrotropin-releasing hormone receptor from GH3 rat anterior pituitary cells. Biochem J, 284: 891-899. [PMID:1377915]

7. Drummond AH, Hughes PJ, Ruiz-Larrea F, Joels LA. (1989) Use of receptor antagonist in elucidating the mechanism of action of TRH in GH3 cells. Ann. N. Y. Acad. Sci., 553: 197-204. [PMID:2566295]

8. Duthie SM, Taylor PL, Anderson L, Cook J, Eidne KA. (1993) Cloning and functional characterisation of the human TRH receptor. Mol Cell Endocrinol, 95: R11-R15. [PMID:8243797]

9. Engel S, Neumann S, Kaur N, Monga V, Jain R, Northup J, Gershengorn MC. (2006) Low Affinity Analogs of Thyrotropin-releasing Hormone Are Super-agonists. J Biol Chem, 281: 13103-13109. [PMID:16551618]

10. Geras-Raaka E, Gershengorn MC. (1987) Measurement of changes in cellular calcium metabolism in response to thyrotropin-releasing hormone. Meth. Enzymol., 141: 36-53. [PMID:3110553]

11. Gershengorn MC, Osman R. (1996) Molecular and cellular biology of thyrotropin-releasing hormone receptors. Physiol. Rev., 76 (1): 175-91. [PMID:8592728]

12. Harder S, Lu X, Wang W, Buck F, Gershengorn MC, Bruhn TO. (2001) Regulator of G protein signaling 4 suppresses basal and thyrotropin releasing-hormone (TRH)-stimulated signaling by two mouse TRH receptors, TRH-R(1) and TRH-R(2). Endocrinology, 142 (3): 1188-94. [PMID:11181534]

13. Hollenberg AN. (2008) The role of the thyrotropin-releasing hormone (TRH) neuron as a metabolic sensor. Thyroid, 18 (2): 131-9. [PMID:18279013]

14. Hsieh KP, Martin TF. (1992) Thyrotropin-releasing hormone and gonadotropin-releasing hormone receptors activate phospholipase C by coupling to the guanosine triphosphate-binding proteins Gq and G11. Mol Endocrinol, 6: 1673-1681. [PMID:1333052]

15. Imai A, Gershengorn MC. (1987) Measurement of lipid turnover in response to thyrotropin-releasing hormone. Meth. Enzymol., 141: 100-1. [PMID:3037241]

16. Itadani H, Nakamura T, Itoh J, Iwaasa H, Kanatani A, Borkowski J, Ihara M, Ohta M. (1998) Cloning and characterization of a new subtype of thyrotropin-releasing hormone receptors. Biochem Biophys Res Commun, 250: 68-71. [PMID:9735333]

17. Matre V, Karlsen HE, Wright MS, Lundell I, Fjeldheim AK, Gabrielsen OS, Larhammar D, Gautvik KM. (1993) Molecular cloning of a functional human thyrotropin-releasing hormone receptor. Biochem Biophys Res Commun, 195: 179-185. [PMID:8395824]

18. O'Dowd BF, Lee DK, Huang W, Nguyen T, Cheng R, Liu Y, Wang B, Gershengorn MC, George SR. (2000) TRH-R2 exhibits similar binding and acute signaling but distinct regulation and anatomic distribution compared with TRH-R1. Mol. Endocrinol., 14 (1): 183-93. [PMID:10628757]

19. Perret G, Valensi P, Hugues JN, Vassy R, Uzzan B. (1988) Use of a pharmacokinetic model to characterize the thyrotropin (TSH) and prolactin (PRL) response to thyrotropin-releasing hormone (THR) in man. Methods Find Exp Clin Pharmacol, 10: 387-391. [PMID:3137402]

20. Rabeler R, Mittag J, Geffers L, Ruther U, Leitges M, Parlow AF, Visser TJ, Bauer K. (2004) Generation of thyrotropin-releasing hormone receptor 1-deficient mice as an animal model of central hypothyroidism. Mol Endocrinol, 18: 1450-1460. [PMID:14988432]

21. Regard JB, Sato IT, Coughlin SR. (2008) Anatomical profiling of G protein-coupled receptor expression. Cell, 135: 561-571. [PMID:18984166]

22. Straub RE, Frech GC, Joho RH, Gershengorn MC. (1990) Expression cloning of a cDNA encoding the mouse pituitary thyrotropin-releasing hormone receptor. Proc Natl Acad Sci U S A, 87: 9514-9518. [PMID:2175902]

23. Taylor RL, Burt DR. (1981) Preparation of 3H-[3-M3-His2]TRH as an improved ligand for TRH receptors. Neuroendocrinology, 32 (5): 310-6. [PMID:6264336]

24. Thirunarayanan N, Nir EA, Raaka BM, Gershengorn MC. (2013) Thyrotropin-releasing hormone receptor type 1 (TRH-R1), not TRH-R2, primarily mediates taltirelin actions in the CNS of mice. Neuropsychopharmacology, 38 (6): 950-6. [PMID:23303050]

25. Thirunarayanan N, Raaka BM, Gershengorn MC. (2012) Taltirelin is a superagonist at the human thyrotropin-releasing hormone receptor. Front Endocrinol (Lausanne), 3: 120. [PMID:23087672]

26. Vale W, Rivier J, Burgus R. (1971) Synthetic TRF (thyrotropin releasing factor) analogues. II. pGlu-N3imMe-His-Pro-NH2: a synthetic analogue with specific activity greater than that of TRF2. Endocrinology, 89 (6): 1485-8. [PMID:5001013]

27. Zabavnik J, Arbuthnott G, Eidne KA. (1993) Distribution of thyrotrophin-releasing hormone receptor messenger RNA in rat pituitary and brain. Neuroscience, 53 (3): 877-87. [PMID:8387653]

28. Zeng H, Schimpf BA, Rohde AD, Pavlova MN, Gragerov A, Bergmann JE. (2007) Thyrotropin-releasing hormone receptor 1-deficient mice display increased depression and anxiety-like behavior. Mol. Endocrinol., 21 (11): 2795-804. [PMID:17666589]

29. Zhao D, Yang J, Jones KE, Gerald C, Suzuki Y, Hogan PG, Chin WW, Tashjian AH. (1992) Molecular cloning of a complementary deoxyribonucleic acid encoding the thyrotropin-releasing hormone receptor and regulation of its messenger ribonucleic acid in rat GH cells. Endocrinology, 130: 3529-3536. [PMID:1317787]

Contributors

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How to cite this page

Marvin Gershengorn.
Thyrotropin-releasing hormone receptors: TRH1 receptor. Last modified on 20/02/2018. Accessed on 18/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=363.