thyrotropin releasing hormone receptors


Summary: Cell surface receptors that bind thyrotropin releasing hormone (TRH) with high affinity and trigger intracellular changes which influence the behavior of cells. Activated TRH receptors in the anterior pituitary stimulate the release of thyrotropin (thyroid stimulating hormone, TSH); TRH receptors on neurons mediate neurotransmission by TRH.

Top Publications

  1. Harder S, Lu X, Wang W, Buck F, Gershengorn M, Bruhn T. 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. 2001;142:1188-94 pubmed
    ..Inhibition of basal signaling of mTRH-R2 by RGS4 suggests that modulation of agonist-independent signaling may be an important mechanism of regulation of G protein-coupled receptor activity under normal physiologic circumstances. ..
  2. Zeng H, Schimpf B, Rohde A, Pavlova M, Gragerov A, Bergmann J. Thyrotropin-releasing hormone receptor 1-deficient mice display increased depression and anxiety-like behavior. Mol Endocrinol. 2007;21:2795-804 pubmed
    ..These results provide the first direct evidence that the endogenous TRH system is involved in mood regulation, and this function is carried out through TRH-R1-mediated neural pathways. ..
  3. Cao J, O Donnell D, Vu H, Payza K, Pou C, Godbout C, et al. Cloning and characterization of a cDNA encoding a novel subtype of rat thyrotropin-releasing hormone receptor. J Biol Chem. 1998;273:32281-7 pubmed
  4. Itadani H, Nakamura T, Itoh J, Iwaasa H, Kanatani A, Borkowski J, et al. Cloning and characterization of a new subtype of thyrotropin-releasing hormone receptors. Biochem Biophys Res Commun. 1998;250:68-71 pubmed
    ..The active metabolite of TRH, histidyl-proline diketopiperazine, or cyclo(His-Pro), showed no specific binding activity. These results suggest that TRHR2 is a novel subtype of TRH receptor. ..
  5. Duthie S, Taylor P, Anderson L, Cook J, Eidne K. Cloning and functional characterisation of the human TRH receptor. Mol Cell Endocrinol. 1993;95:R11-5 pubmed
    ..COS-1 cells expressing the human TRH-R showed high affinity receptor binding. Stimulation of these cells with TRH produced a typical phosphoinositide response and mobilisation of intracellular calcium [Ca2+]i. ..
  6. de la Pena P, Delgado L, del Camino D, Barros F. Two isoforms of the thyrotropin-releasing hormone receptor generated by alternative splicing have indistinguishable functional properties. J Biol Chem. 1992;267:25703-8 pubmed
    ..Functional expression in Xenopus laevis oocytes indicates that both cDNAs encode fully functional TRH receptors. Otherwise, indistinguishable electrophysiological responses to TRH are evoked in oocytes expressing both receptor isoforms. ..
  7. Sellar R, Taylor P, Lamb R, Zabavnik J, Anderson L, Eidne K. Functional expression and molecular characterization of the thyrotrophin-releasing hormone receptor from the rat anterior pituitary gland. J Mol Endocrinol. 1993;10:199-206 pubmed
    ..The sequence given for the 3'-untranslated region is 1.5 kb longer than that reported for the mouse receptor, and extends to the poly(A) tail. ..
  8. Sun Y, Lu X, Gershengorn M. Thyrotropin-releasing hormone receptors -- similarities and differences. J Mol Endocrinol. 2003;30:87-97 pubmed
    ..These differences in signaling and internalization properties are probably important in the distinct parts that TRH-R1 and TRH-R2 may play in mammalian physiology. ..
  9. Yamada M, Shibusawa N, Hashida T, Ozawa A, Monden T, Satoh T, et al. Expression of thyrotropin-releasing hormone (TRH) receptor subtype 1 in mouse pancreatic islets and HIT-T15, an insulin-secreting clonal beta cell line. Life Sci. 2000;66:1119-25 pubmed

More Information


  1. Takata M, Shimada Y, Ikeda A, Sekikawa K. Molecular cloning of bovine thyrotropin-releasing hormone receptor gene. J Vet Med Sci. 1998;60:123-7 pubmed
    ..The identity of the deduced amino acid sequence of bovine TRHR exceeded 88% that of mouse, rat or human. RT-PCR analysis indicated TRHR mRNA to be expressed in the pituitary and brain. ..
  2. Rabeler R, Mittag J, Geffers L, Ruther U, Leitges M, Parlow A, et al. Generation of thyrotropin-releasing hormone receptor 1-deficient mice as an animal model of central hypothyroidism. Mol Endocrinol. 2004;18:1450-60 pubmed
  3. Straub R, Frech G, Joho R, Gershengorn M. Expression cloning of a cDNA encoding the mouse pituitary thyrotropin-releasing hormone receptor. Proc Natl Acad Sci U S A. 1990;87:9514-8 pubmed
    ..The 3.8-kilobase mouse TRH-R cDNA encodes a protein of 393 amino acids that shows similarities to other guanine nucleotide-binding regulatory protein-coupled receptors. ..
  4. Luo L, Yano N. Expression of thyrotropin-releasing hormone receptor in immortalized beta-cell lines and rat pancreas. J Endocrinol. 2004;181:401-12 pubmed
    ..Our observations suggested that the biological role of TRH in pancreatic beta-cells is via the activation of TRHR1. Further research is required to identify the role of TRHR1 in the pancreas aside from the islets. ..
  5. Matre V, Karlsen H, Wright M, Lundell I, Fjeldheim A, Gabrielsen O, et al. Molecular cloning of a functional human thyrotropin-releasing hormone receptor. Biochem Biophys Res Commun. 1993;195:179-85 pubmed
    ..The predicted amino acid sequence of the hTRH-R protein showed high homology with the rat and mouse TRH-Rs with the exception of their C-terminal region. The human TRH-R gene seems to contain two introns. ..
  6. Sun Y, Millar R, Ho H, Gershengorn M, Illing N. Cloning and characterization of the chicken thyrotropin-releasing hormone receptor. Endocrinology. 1998;139:3390-8 pubmed
    ..This study provides a useful tool for further studies on the roles of TRH in avian growth and TSH regulation. ..
  7. Zhao D, Yang J, Jones K, Gerald C, Suzuki Y, Hogan P, et al. 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. 1992;130:3529-36 pubmed
    ..We conclude that the rTRHR shares high primary sequence similarity to the mTRHR, but the rTRHR has an extension of 19 amino acids at its carboxy-terminus, which is lacking in the mTRHR. ..
  8. Harder S, Dammann O, Buck F, Zwiers H, Lederis K, Richter D, et al. Cloning of two thyrotropin-releasing hormone receptor subtypes from a lower vertebrate (Catostomus commersoni): functional expression, gene structure, and evolution. Gen Comp Endocrinol. 2001;124:236-45 pubmed
    ..A common ancestral TRH receptor gene that could be found much earlier in evolution, possibly in invertebrates, might be the origin of ccTRH-R genes. ..
  9. Engel S, Gershengorn M. Thyrotropin-releasing hormone and its receptors--a hypothesis for binding and receptor activation. Pharmacol Ther. 2007;113:410-9 pubmed
    ..This hypothesis represents a starting point for understanding the biology of the TRH/TRH-R system on a molecular level and provides a basis for potential design of new potent and selective modulators of TRH-R's activity. ..
  10. Asai H, Asahi T, Yamamura M, Yamauchi Kohno R, Saito A. Lack of behavioral tolerance by repeated treatment with taltirelin hydrate, a thyrotropin-releasing hormone analog, in rats. Pharmacol Biochem Behav. 2005;82:646-51 pubmed
    ..Thus, the down-regulation of TRH receptors would be a main cause of the behavioral tolerance. These results suggest that taltirelin hardly develops the behavioral tolerance due to the lack of down-regulation of TRH receptors. ..
  11. Baeza M, Ponce G, Joseph Bravo P, Charli J. Rapid down regulation of pyroglutamyl peptidase II activity by arachidonic acid in primary cultures of adenohypophyseal cells. Life Sci. 2001;68:2051-60 pubmed
    ..This is the first evidence that AA mobilization can regulate the activity of an ectopeptidase. ..
  12. Gershengorn M, Osman R. Minireview: Insights into G protein-coupled receptor function using molecular models. Endocrinology. 2001;142:2-10 pubmed
    ..The success of this approach is due to the synergistic interaction between theory and experiment. ..
  13. Miranda P, Giraldez T, de la Pena P, Manso D, Alonso Ron C, Gomez Varela D, et al. Specificity of TRH receptor coupling to G-proteins for regulation of ERG K+ channels in GH3 rat anterior pituitary cells. J Physiol. 2005;566:717-36 pubmed
  14. Perlman J, Colson A, Jain R, Czyzewski B, Cohen L, Osman R, et al. Role of the extracellular loops of the thyrotropin-releasing hormone receptor: evidence for an initial interaction with thyrotropin-releasing hormone. Biochemistry. 1997;36:15670-6 pubmed
    ..We suggest that a role of the ECLs in all G protein-coupled receptors for small ligands may be to initially contact the ligand and allow entry into a TM binding pocket. ..
  15. Carroll A, Lamb J, Moni R, Hooper J, Quinn R. Spongian diterpenes with thyrotropin releasing hormone receptor 2 binding affinity from Spongia sp. J Nat Prod. 2008;71:884-6 pubmed publisher
    ..Diterpenes 1-5 showed rat TRH receptor 2 binding affinity with IC(50) values of 23 microM, 70 microM, 400 microM, 600 microM, and 1 mM, respectively. ..
  16. Suzuki S, Pilowsky P, Minson J, Arnolda L, Llewellyn Smith I, Chalmers J. Antisense to thyrotropin releasing hormone receptor reduces arterial blood pressure in spontaneously hypertensive rats. Circ Res. 1995;77:679-83 pubmed
  17. Satoh T, Feng P, Wilber J. A truncated isoform of the thyrotropin-releasing hormone receptor is expressed in the rat central nervous system as well as in the pituitary gland. Brain Res Mol Brain Res. 1993;20:353-6 pubmed
    ..This truncated TRH-R mRNA, along with the longer receptor form, was found to be expressed throughout the rat pituitary gland and brain. ..
  18. Kadam R, Chavan A, Monga V, Kaur N, Jain R, Roy N. Selectivity-based QSAR approach for screening and evaluation of TRH analogs for TRH-R1 and TRH-R2 receptors subtypes. J Mol Graph Model. 2008;27:309-20 pubmed publisher
    ..The statistically significant predictive models were thoroughly validated using an external validation set whose activity was previously unknown. The model was able to predict preference for either of the receptor subtypes successfully. ..
  19. Kocan M, See H, Seeber R, Eidne K, Pfleger K. Demonstration of improvements to the bioluminescence resonance energy transfer (BRET) technology for the monitoring of G protein-coupled receptors in live cells. J Biomol Screen. 2008;13:888-98 pubmed publisher
  20. Narayanan C, Fujimoto J, Geras Raaka E, Gershengorn M. Regulation by thyrotropin-releasing hormone (TRH) of TRH receptor mRNA degradation in rat pituitary GH3 cells. J Biol Chem. 1992;267:17296-303 pubmed
    ..We present an hypothesis that explains specific regulation of TRH-R mRNA degradation by TRH in GH3 pituitary cells. ..
  21. Collazos A, Diouf B, Guerineau N, Quittau Prevostel C, Peter M, Coudane F, et al. A spatiotemporally coordinated cascade of protein kinase C activation controls isoform-selective translocation. Mol Cell Biol. 2006;26:2247-61 pubmed
    ..These results challenge the current understanding of PKC signaling and raise the question of a functional dependence between isoforms. ..
  22. Ishibashi H, Nakahata Y, Eto K, Nabekura J. Excitation of locus coeruleus noradrenergic neurons by thyrotropin-releasing hormone. J Physiol. 2009;587:5709-22 pubmed publisher
    ..The action of TRH on LC neurons may influence a variety of CNS functions related to the noradrenergic system which include arousal and analgesia. ..
  23. Oshita F, Sekiyama A, Saito H, Yamada K, Noda K, Miyagi Y. Genome-wide cDNA microarray screening of genes related to the benefits of paclitaxel and irinotecan chemotherapy in patients with advanced non-small cell lung cancer. J Exp Ther Oncol. 2006;6:49-53 pubmed
    ..In conclusion, the expression of certain genes was able to predict the benefits of this Pac and CPT chemotherapy regimen. ..
  24. Zhang W, Berglund A, Kao J, Couty J, Gershengorn M, Marshall G. Impact of azaproline on amide cis-trans isomerism: conformational analyses and NMR studies of model peptides including TRH analogues. J Am Chem Soc. 2003;125:1221-35 pubmed
  25. Yamada M, Hashimoto K, Satoh T, Shibusawa N, Kohga H, Ozawa Y, et al. A novel transcript for the thyrotropin-releasing hormone receptor in human pituitary and pituitary tumors. J Clin Endocrinol Metab. 1997;82:4224-8 pubmed
    ..These findings indicate that this novel transcript of the human TRH receptor gene is produced in a tumor-specific manner and may be a useful parameter for evaluation of individual pituitary tumors. ..
  26. Arai K, Sahara Y, Suzuki H, Kimura N. Estradiol transcriptionally and posttranscriptionally up-regulates thyrotropin-releasing hormone receptor messenger ribonucleic acid in rat pituitary cells. Endocrinology. 1994;134:432-40 pubmed
    ..3 to 4.4 h). These results demonstrate that E2 up-regulates the TRH receptors of the pituitary cells at the mRNA level by increasing both the transcription rate and stability. ..
  27. Petrou C, Tashjian A. The thyrotropin-releasing hormone-receptor complex and G11alpha are both internalised into clathrin-coated vesicles. Cell Signal. 1998;10:553-9 pubmed
    ..We conclude that, after agonist-induced TRHR-G11alpha coupling, both the TRH-TRHR complex and G11alpha are internalised in CCVs...
  28. Hanyaloglu A, Vrecl M, Kroeger K, Miles L, Qian H, Thomas W, et al. Casein kinase II sites in the intracellular C-terminal domain of the thyrotropin-releasing hormone receptor and chimeric gonadotropin-releasing hormone receptors contribute to beta-arrestin-dependent internalization. J Biol Chem. 2001;276:18066-74 pubmed
    ..This study presents evidence of a novel role for C-tail CKII consensus sites in targeting these GPCRs to the beta-arrestin-dependent pathway. ..
  29. Lipinsky D, Gershengorn M, Oron Y. Latency in the inositol lipid transduction pathway: the role of cellular events in responses to thyrotropin-releasing hormone in Xenopus oocytes. Pflugers Arch. 1993;425:140-9 pubmed
    ..We propose that this process is kinetically controlled by an early rate-limiting event, involving the activation of a guanine nucleotide-binding protein by the TRH receptor. ..
  30. Das S, Bhargava H. Inhibition of [3H][3-MeHis2]thyrotropin releasing hormone recognition sites in the rat brain by tifluadom, a kappa opiate receptor agonist. Neuropharmacology. 1987;26:1141-6 pubmed
    ..The effect does not appear to be mediated through benzodiazepine receptors but possibly through kappa-opiate receptors.(ABSTRACT TRUNCATED AT 250 WORDS) ..
  31. Kostic T, Tomic M, Andric S, Stojilkovic S. Calcium-independent and cAMP-dependent modulation of soluble guanylyl cyclase activity by G protein-coupled receptors in pituitary cells. J Biol Chem. 2002;277:16412-8 pubmed
  32. Prokai Tatrai K, Perjesi P, Zharikova A, Li X, Prokai L. Design, synthesis, and biological evaluation of novel, centrally-acting thyrotropin-releasing hormone analogues. Bioorg Med Chem Lett. 2002;12:2171-4 pubmed
    ..No binding to the endocrine TRH-receptor was measured for 2a; thus, this compound emerged as a potent, centrally acting TRH analogue. ..
  33. Sattin A, Senanayake S, Pekary A. Lithium modulates expression of TRH receptors and TRH-related peptides in rat brain. Neuroscience. 2002;115:263-73 pubmed
    ..The present results are consistent with a component role for TRH and related peptides in the mood-altering effects of lithium administration and withdrawal frequently observed during treatment for depression and bipolar disorder. ..
  34. Sun Y, Zupan B, Raaka B, Toth M, Gershengorn M. TRH-receptor-type-2-deficient mice are euthyroid and exhibit increased depression and reduced anxiety phenotypes. Neuropsychopharmacology. 2009;34:1601-8 pubmed publisher
  35. Zwermann O, Suttmann Y, Bidlingmaier M, Beuschlein F, Reincke M. Screening for membrane hormone receptor expression in primary aldosteronism. Eur J Endocrinol. 2009;160:443-51 pubmed publisher
    ..A good correlation between clinical and molecular testing could be observed, making an involvement of the receptor expressed in PA possible. ..
  36. Carroll A, Urban S, Lamb J, Moni R, Guymer G, Forster P, et al. Corymbones A and B, phloroglucinols with thyrotropin releasing hormone receptor 2 binding affinity from the flowers of Corymbia peltata. J Nat Prod. 2008;71:881-3 pubmed publisher
    ..Their structures were assigned from interpretation of 2D NMR and high-resolution ESIMS data. Compounds 1 and 2 showed rat TRH receptor 2 binding affinity with IC 50 values of 23 and 19 microM, respectively. ..
  37. Jones B, Hinkle P. Subcellular trafficking of the TRH receptor: effect of phosphorylation. Mol Endocrinol. 2009;23:1466-78 pubmed publisher
  38. Jaimes Hoy L, Joseph Bravo P, de Gortari P. Differential response of TRHergic neurons of the hypothalamic paraventricular nucleus (PVN) in female animals submitted to food-restriction or dehydration-induced anorexia and cold exposure. Horm Behav. 2008;53:366-77 pubmed publisher
  39. Tsai S, Tang T, Wang P. Interrelationship between estradiol and thyroxine on the release of thyrotropin and prolactin in ovariectomized-thyroidectomized rats. Chin J Physiol. 1992;35:55-65 pubmed
    ..The interaction between estradiol and thyroxine on serum prolactin and TSH levels was not reflected by the interaction between these two hormones on the anterior pituitary gland. ..
  40. Durchankova D, Novotny J, Svoboda P. The time-course of agonist-induced solubilization of trimeric G(q)alpha/G(11)alpha proteins resolved by two-dimensional electrophoresis. Physiol Res. 2008;57:195-203 pubmed
    ..Our data therefore rather indicate tight/persisting binding of G(q)alpha/G(11)alpha proteins to the membrane. ..
  41. Duthie S, Taylor P, Eidne K. Characterization of the mouse thyrotrophin-releasing hormone receptor gene: an exon corresponds to a deletion in the rat cDNA. J Mol Endocrinol. 1993;11:141-9 pubmed
    ..abstract truncated at 250 words) ..
  42. Kaur N, Monga V, Lu X, Gershengorn M, Jain R. Modifications of the pyroglutamic acid and histidine residues in thyrotropin-releasing hormone (TRH) yield analogs with selectivity for TRH receptor type 2 over type 1. Bioorg Med Chem. 2007;15:433-43 pubmed
  43. de Gortari P, Uribe R, García Vázquez A, Aguilar Valles A, Martinez A, Valdes A, et al. Amygdala kindling differentially regulates the expression of the elements involved in TRH transmission. Neurochem Int. 2006;48:31-42 pubmed
    ..They show that reported changes in PPII activity or TRH-binding caused by kindling relate to regulation of the expression of TRH receptors and degrading enzyme. ..
  44. McFarlane D, Beech J, Cribb A. Alpha-melanocyte stimulating hormone release in response to thyrotropin releasing hormone in healthy horses, horses with pituitary pars intermedia dysfunction and equine pars intermedia explants. Domest Anim Endocrinol. 2006;30:276-88 pubmed
    ..The increase in plasma cortisol following TRH in horses with PPID is likely attributable to the release of ACTH from the hyperplastic PI. ..
  45. Scott M, Benmerah A, Muntaner O, Marullo S. Recruitment of activated G protein-coupled receptors to pre-existing clathrin-coated pits in living cells. J Biol Chem. 2002;277:3552-9 pubmed
  46. Ostasov P, Krusek J, Durchankova D, Svoboda P, Novotny J. Ca2+ responses to thyrotropin-releasing hormone and angiotensin II: the role of plasma membrane integrity and effect of G11alpha protein overexpression on homologous and heterologous desensitization. Cell Biochem Funct. 2008;26:264-74 pubmed
  47. Yamada M, Shibusawa N, Ishii S, Horiguchi K, Umezawa R, Hashimoto K, et al. Prolactin secretion in mice with thyrotropin-releasing hormone deficiency. Endocrinology. 2006;147:2591-6 pubmed
  48. Ogiwara T, Murakami M. [Central hypothyroidism]. Nihon Rinsho. 2005;63 Suppl 10:93-8 pubmed
  49. Carroll A, Lamb J, Moni R, Guymer G, Forster P, Quinn R. Myrtucommulones F-I, phloroglucinols with thyrotropin-releasing hormone receptor-2 binding affinity from the seeds of Corymbia scabrida. J Nat Prod. 2008;71:1564-8 pubmed publisher
    ..The structure of myrtucommulone D (2) has been revised. Myrtucommulones A, D, and F-I showed rat TRH receptor-2 binding affinity with IC50 values of 39, 11, 16, 24, 31, and 16 microM, respectively. ..
  50. Kozlowski M. Inhibition of the binding and the behavioral effects of thyrotropin-releasing hormone (TRH) by the triazolobenzodiazepines. Pharmacol Biochem Behav. 1988;30:73-5 pubmed
    ..However, this action is not necessarily linked to its inhibition of TRH receptor binding since alprazolam also inhibited the narcoleptic effect of amphetamine. ..
  51. Rudajev V, Novotny J, Hejnova L, Milligan G, Svoboda P. Dominant portion of thyrotropin-releasing hormone receptor is excluded from lipid domains. Detergent-resistant and detergent-sensitive pools of TRH receptor and Gqalpha/G11alpha protein. J Biochem. 2005;138:111-25 pubmed
    ..Trimeric G protein G(q)alpha/G(11)alpha occurs in both DRMs and in the bulk of plasma membranes, which is totally solubilized by TX-100. ..
  52. Lu X, Huang W, Worthington S, Drabik P, Osman R, Gershengorn M. A model of inverse agonist action at thyrotropin-releasing hormone receptor type 1: role of a conserved tryptophan in helix 6. Mol Pharmacol. 2004;66:1192-200 pubmed
    ..We suggest that the mechanism of inverse agonism effected by midazolam involves its direct interaction with Trp-279, which contributes to the stabilization of the inactive conformation of TRH-R1. ..
  53. Gomez Varela D, Barros F, Viloria C, Giraldez T, Manso D, Dupuy S, et al. Relevance of the proximal domain in the amino-terminus of HERG channels for regulation by a phospholipase C-coupled hormone receptor. FEBS Lett. 2003;535:125-30 pubmed
    ..Thus, whereas residues 326-345 are required for the hormonal modulation of HERG activation, different proximal domain sequences contribute to set HERG gating characteristics and its regulation by TRH. ..