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Gene and Protein Information  |
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| 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 16.82 cM | 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 |
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| Specialist databases | |
| GPCRdb | trfr_human (Hs), trfr_mouse (Mm), trfr_rat (Rn) |
| Other databases | |
| Alphafold | P34981 (Hs), P21761 (Mm), Q01717 (Rn) |
| ChEMBL Target | CHEMBL1810 (Hs), CHEMBL2467 (Mm), CHEMBL4553 (Rn) |
| Ensembl Gene | ENSG00000174417 (Hs), ENSMUSG00000038760 (Mm), ENSRNOG00000005048 (Rn) |
| Entrez Gene | 7201 (Hs), 22045 (Mm), 25570 (Rn) |
| Human Protein Atlas | ENSG00000174417 (Hs) |
| KEGG Gene | hsa:7201 (Hs), mmu:22045 (Mm), rno:25570 (Rn) |
| OMIM | 188545 (Hs) |
| Orphanet | ORPHA120261 (Hs) |
| Pharos | P34981 (Hs) |
| RefSeq Nucleotide | NM_003301 (Hs), NM_013696 (Mm), NM_013047 (Rn) |
| RefSeq Protein | NP_003292 (Hs), NP_038724 (Mm), NP_037179 (Rn) |
| UniProtKB | P34981 (Hs), P21761 (Mm), Q01717 (Rn) |
| Wikipedia | TRHR (Hs) |
| 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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| 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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| View species-specific antagonist tables | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Antagonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Newer antagonists have been reported but are not readily available. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary Transduction Mechanisms
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| Transducer | Effector/Response |
| Gq/G11 family | Phospholipase C stimulation |
| References: 1,14 | |
| Tissue Distribution
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| Expression Datasets |
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| Functional Assays
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| Physiological Functions
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| 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
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| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||||||||||||||
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| Clinically-Relevant Mutations and Pathophysiology
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| General Comments |
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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. |
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 (35): 24983-8. [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 et al.. (1998) Cloning and characterization of a cDNA encoding a novel subtype of rat thyrotropin-releasing hormone receptor. J Biol Chem, 273 (48): 32281-7. [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 Peña 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 ( Pt 3): 891-9. [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 (1-2): R11-5. [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 (19): 13103-9. [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 (10): 1673-81. [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 (1): 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 (1): 179-85. [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 (6): 387-91. [PMID:3137402]
20. Rabeler R, Mittag J, Geffers L, Rüther 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 (6): 1450-60. [PMID:14988432]
21. Regard JB, Sato IT, Coughlin SR. (2008) Anatomical profiling of G protein-coupled receptor expression. Cell, 135 (3): 561-71. [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 USA, 87 (24): 9514-8. [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 Jr 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 (6): 3529-36. [PMID:1317787]
