Thyrotropin-releasing hormone receptors: Introduction

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General

Thyrotropin-releasing hormone (TRH) is a tripeptide, pyroGlu-His-Proamide, that is synthesized in the hypothalamus and released into the hypothalamic-pituitary portal circulation to act on the pituitary [2-3] TRH is produced in many other tissues, especially within the nervous system, where it appears to act as a neurotransmitter/neuromodulator. TRH appears to initiate all of these effects by interacting with receptors that belong to the Class A G protein-coupled receptor (GPCR) family. In 1990, the first TRH receptor (TRH-R), later named type 1 TRH receptor, TRH1, was cloned from a mouse pituitary tumor cDNA library [16] and then orthologous receptors were cloned from a number of different species including rat [5,20], chicken, cow, catostomus commersoni and humans [7,14]. The human TRH receptor, TRHR), is 90.3% and 89.2% homologous to the mouse and rat type 1 receptors at the DNA level, respectively; the three receptors exhibit approximately 95% homology at the amino acid level. In 1998, a second subtype of the TRH receptor (TRH2) was identified in rat [4,13,15], mouse [11] and several other species; TRH2 has not been found in humans. Amino acid sequence alignments of the two types of TRH receptors from the same species reveal a 50% overall identity. Of note, most of the structural research on TRH receptors has been performed with TRH1.

TRH1 signalling

TRH1 signal transduction is mediated primarily by coupling to Gq/11 proteins [1,12]. TRH1 activation leads to stimulation of phosphoinositide-specific phospholipase C, which stimulates phosphatidylinositol 4,5-P2(PIP2) hydrolysis to form inositol 1,4,5-triphosphosphate (IP3) and 1,2-diacylglycerol (DAG). These second messengers stimulate increases in intracellular calcium and activation of protein kinase C. TRH1 also stimulates calcium/calmodulin-dependent protein kinase and mitogen-activated protein kinase. TRH1 also appears to couple to Gi2, Gi3, and to a Gs-like protein that does not activate adenylyl cyclase. Although TRH1 and TRH2 signal via the same pathways, these receptors show marked differences in basal signalling activities in that TRH2 exhibits marked TRH-independent signalling activity [19].

TRH1 structure

A model of mouse TRH1 has been constructed based on homology to the x-ray crystallographic structure of bovine rhodopsin that appears to be a good model for TRH1 because a number of its predictions have been shown by experimentation to be correct [10]. The model of the binding pocket of TRH1 showed that the positions of Tyr106 in transmembrane helix -3 (TMH-3), Tyr282 in TMH-6, and Arg306 in TMH-7 are important for TRH binding. This model placed the binding pocket for TRH in the upper half of the transmembrane domain. This binding pocket location is similar to those found for small nonpeptide ligands.

Pharmacology

TRH is the only known naturally-occurring, high affinity ligand for TRH receptors. Of the many TRH analogues synthesized, only (Nτ-methyl)His-TRH (MeTRH) has been shown to exhibit a higher affinity at TRH receptors than TRH [18]. Recently, it was shown that several TRH analogues with affinities lower than TRH exhibited higher efficacies than TRH at TRH1 [8,17]. There are several small organic compounds that act as antagonists at TRH receptors but with relatively low affinity [6,9,19].

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 (35): 24983-8. [PMID:1334076]

2. Boler J, Enzmann F, Folkers K, Bowers CY, Schally AV. (1969) The identity of chemical and hormonal properties of the thyrotropin releasing hormone and pyroglutamyl-histidyl-proline amide. Biochem. Biophys. Res. Commun., 37 (4): 705-10. [PMID:4982117]

3. Burgus R, Dunn TF, Desiderio D, Ward DN, Vale W, Guillemin R. (1970) Characterization of ovine hypothalamic hypophysiotropic TSH-releasing factor. Nature, 226 (5243): 321-5. [PMID:4985794]

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. 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]

6. 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]

7. 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]

8. 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]

9. Engel S, Skoumbourdis AP, Childress J, Neumann S, Deschamps JR, Thomas CJ, Colson AO, Costanzi S, Gershengorn MC. (2008) A virtual screen for diverse ligands: discovery of selective G protein-coupled receptor antagonists. J. Am. Chem. Soc., 130 (15): 5115-23. [PMID:18357984]

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

11. 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]

12. 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]

13. 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]

14. 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]

15. 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]

16. 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 (24): 9514-8. [PMID:2175902]

17. 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]

18. 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]

19. Wang W, Gershengorn MC. (1999) Rat TRH receptor type 2 exhibits higher basal signaling activity than TRH receptor type 1. Endocrinology, 140 (10): 4916-9. [PMID:10499553]

20. 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]

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