Thyrotropin-releasing hormone (TRH) is an important endocrine agent that regulates the function of cells in the anterior pituitary and the central and peripheral nervous systems. By controlling the synthesis and release of thyroid hormones, TRH affects many physiological functions, including energy homeostasis. This hormone exerts its effects through G protein-coupled TRH receptors, which signal primarily through Gq/11 but may also utilize other G protein classes under certain conditions. Because of the potential therapeutic benefit, considerable attention has been devoted to the synthesis of new TRH analogs that may have some advantageous properties compared with TRH. In this context, it may be interesting to consider the phenomenon of biased agonism and signaling at the TRH receptor. This possibility is supported by some recent findings. Although knowledge about the mechanisms of TRH receptor-mediated signaling has increased steadily over the past decades, there are still many unanswered questions, particularly about the molecular details of post-receptor signaling. In this review, we summarize what has been learned to date about TRH receptor-mediated signaling, including some previously undiscussed information, and point to future directions in TRH research that may offer new insights into the molecular mechanisms of TRH receptor-triggered actions and possible ways to modulate TRH receptor-mediated signaling.

Department of Physiology Faculty of Science Charles University Prague Czechia

Zobrazit více v PubMed

Altobelli G. G., Van Noorden S., Cimini D., Illario M., Sorriento D., Cimini V. (2021). Calcium/calmodulin-dependent kinases can regulate the TSH expression in the rat pituitary. J. Endocrinol. Invest. 44 (11), 2387–2394. 10.1007/s40618-021-01545-0 PubMed DOI

Anderson L., Alexander C. L., Faccenda E., Eidne K. A. (1995). Rapid desensitization of the thyrotropin-releasing-hormone receptor expressed in single human-embryonal-kidney-293-cells. Biochem. J. 311 (2), 385–392. 10.1042/bj3110385 PubMed DOI PMC

Arnold R., Klingberg F., Schäker W. (1991). Systemically applied thyrotropin-releasing hormone (TRH) modifies spontaneous behaviour of rats. Biomed. Biochim. Acta 50 (12), 1217–1224. PubMed

Ashworth R., Yu R., Nelson E. J., Dermer S., Gershengorn M. C., Hinkle P. M. (1995). Visualization of the thyrotropin-releasing-hormone receptor and its ligand during endocytosis and recycling. Proc. Natl. Acad. Sci. U. S. A. 92 (2), 512–516. 10.1073/pnas.92.2.512 PubMed DOI PMC

Banihashemi B., Albert P. R. (2002). Dopamine-D2S receptor inhibition of calcium influx, adenylyl cyclase, and mitogen-activated protein kinase in pituitary cells: distinct galpha and gbetagamma requirements. Mol. Endocrinol. 16 (10), 2393–2404. 10.1210/me.2001-0220 PubMed DOI

Barros F., Gomez-Varela D., Viloria C. G., Palomero T., Giráldez T., de la Peña P. (1998). Modulation of human erg K+ channel gating by activation of a G protein-coupled receptor and protein kinase C. J. Physiol. 511 (2), 333–346. 10.1111/j.1469-7793.1998.333bh.x PubMed DOI PMC

Bonomi M., Busnelli M., Beck-Peccoz P., Costanzo D., Antonica F., Dolci C., et al. (2009). A family with complete resistance to thyrotropin-releasing hormone. N. Engl. J. Med. 360 (7), 731–734. 10.1056/NEJMc0808557 PubMed DOI

Boutin A., Allen M. D., Neumann S., Gershengorn M. C. (2012). Persistent signaling by thyrotropin-releasing hormone receptors correlates with G-protein and receptor levels. FASEB J. 26 (8), 3473–3482. 10.1096/fj.12-207860 PubMed DOI PMC

Brejchová J., Sýkora J., Ostašov P., Merta L., Roubalová L., Janáček J., et al. (2015). TRH-receptor mobility and function in intact and cholesterol-depleted plasma membrane of HEK293 cells stably expressing TRH-R-eGFP. Biochim. Biophys. Acta 1848 (3), 781–796. 10.1016/j.bbamem.2014.11.029 PubMed DOI

Brozmanova H., Langer P., Knopp J., Foldes O. (1980). Changes in adenylate-cyclase activity in rat pituitary after TRH and T3 injection invivo. Acta Endocrinol. 95 (2), 166–171. 10.1530/acta.0.0950166 PubMed DOI

Cabana J., Holleran B., Leduc R., Escher E., Guillemette G., Lavigne P. (2015). Identification of distinct conformations of the angiotensin-II type 1 receptor associated with the gq/11 protein pathway and the β-arrestin pathway using molecular dynamics simulations. J. Biol. Chem. 290 (25), 15835–15854. 10.1074/jbc.M114.627356 PubMed DOI PMC

Caroscio J. T., Cohen J. A., Zawodniak J., Takai V., Shapiro A., Blaustein S., et al. (1986). A double-blind, placebo-controlled trial of TRH in amyotrophic lateral sclerosis. Neurology 36 (2), 141–145. 10.1212/wnl.36.2.141 PubMed DOI

Carretero L., Barros F., Miranda P., Fernández-Trillo J., Machín A., de la Peña P., et al. (2012). Cell type influences the molecular mechanisms involved in hormonal regulation of ERG K+ channels. Pflugers Arch. 463 (5), 685–702. 10.1007/s00424-012-1094-y PubMed DOI

Carretero L., Llavona P., Lopez-Hernandez A., Casado P., Cutillas P. R., de la Pena F., et al. (2015). ERK and RSK are necessary for TRH-induced inhibition of r-ERG potassium currents in rat pituitary GH(3) cells. Cell. Signal. 27 (9), 1720–1730. 10.1016/j.cellsig.2015.05.014 PubMed DOI

Cassier E., Gallay N., Bourquard T., Claeysen S., Bockaert J., Crepieux P., et al. (2017). Phosphorylation of beta-arrestin2 at Thr(383) by MEK underlies beta-arrestin-dependent activation of Erk1/2 by GPCRs. Elife 6, e23777. 10.7554/eLife.23777 PubMed DOI PMC

Choi Y. H., Hartzell D., Azain M. J., Baile C. A. (2002). TRH decreases food intake and increases water intake and body temperature in rats. Physiol. Behav. 77 (1), 1–4. 10.1016/s0031-9384(02)00784-9 PubMed DOI

Coffa S., Breitman M., Hanson S. M., Callaway K., Kook S., Dalby K. N., et al. (2011). The effect of arrestin conformation on the recruitment of c-raf1, MEK1, and ERK1/2 activation. PLoS ONE 6 (12), e28723. 10.1371/journal.pone.0028723 PubMed DOI PMC

Collu R., Tang J., Castagné J., Lagacé G., Masson N., Huot C., 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), 1561–1565. 10.1210/jcem.82.5.3918 PubMed DOI

Cook J. V. F., McGregor A., Lee T. W., Milligan G., Eidne K. A. (1996). A disulfide bonding interaction role for cysteines in the extracellular domain of the thyrotropin-releasing hormone receptor. Endocrinology 137 (7), 2851–2858. 10.1210/endo.137.7.8770906 PubMed DOI

Cook L. B., Hinkle P. M. (2004a). Agonist-dependent up-regulation of thyrotrophin-releasing hormone receptor protein. Biochem. J. 380 (3), 815–821. 10.1042/BJ20031467 PubMed DOI PMC

Cook L. B., Hinkle P. M. (2004b). Fate of internalized thyrotropin-releasing hormone receptors monitored with a timer fusion protein. Endocrinology 145 (7), 3095–3100. 10.1210/en.2004-0304 PubMed DOI

Cook L. B., Zhu C. C., Hinkle P. M. (2003). Thyrotropin-releasing hormone receptor processing: role of ubiquitination and proteasomal degradation. Mol. Endocrinol. 17 (9), 1777–1791. 10.1210/me.2003-0073 PubMed DOI

Daimon C. M., Chirdon P., Maudsley S., Martin B. (2013). The role of Thyrotropin Releasing Hormone in aging and neurodegenerative diseases. Am. J. Alzheimers Dis. (Columbia) 1 (1), 1003. 10.7726/ajad.2013.1003 PubMed DOI PMC

Day P. W., Carman C. V., Sterne-Marr R., Benovic J. L., Wedegaertner P. B. (2003). Differential interaction of GRK2 with members of the G alpha q family. Biochemistry 42 (30), 9176–9184. 10.1021/bi034442+ PubMed DOI

de la Peña P., del Camino D., Pardo L. A., Domínguez P., Barros F. (1995). Gs couples thyrotropin-releasing hormone receptors expressed in Xenopus oocytes to phospholipase C. J. Biol. Chem. 270 (8), 3554–3559. 10.1074/jbc.270.8.3554 PubMed DOI

de la Peña P., Delgado L. M., del Camino D., Barros F. (1992). Two isoforms of the thyrotropin-releasing hormone receptor generated by alternative splicing have indistinguishable functional properties. J. Biol. Chem. 267 (36), 25703–25708. 10.1016/s0021-9258(18)35664-3 PubMed DOI

Deflorian F., Engel S., Colson A. O., Raak a. B. M., Gershengorn M. C., Costanzi S. (2008). Understanding the structural and functional differences between mouse thyrotropin-releasing hormone receptors 1 and 2. Proteins 71 (2), 783–794. 10.1002/prot.21763 PubMed DOI

Deng P. Y., Porter J. E., Shin H. S., Lei S. (2006). Thyrotropin-releasing hormone increases GABA release in rat hippocampus. J. Physiol. 577 (2), 497–511. 10.1113/jphysiol.2006.118141 PubMed DOI PMC

Dijkman P. M., Castell O. K., Goddard A. D., Munoz-Garcia J. C., de Graaf C., Wallace M. I., et al. (2018). Dynamic tuneable G protein-coupled receptor monomer-dimer populations. Nat. Commun. 9 (1), 1710. 10.1038/s41467-018-03727-6 PubMed DOI PMC

Dong Q., Brucker-Davis F., Weintraub B. D., Smallridge R. C., Carr F. E., Battey J., et al. (1996). Screening of candidate oncogenes in human thyrotroph tumors: absence of activating mutations of the G alpha q, G alpha 11, G alpha s, or thyrotropin-releasing hormone receptor genes. J. Clin. Endocrinol. Metab. 81 (3), 1134–1140. 10.1210/jcem.81.3.8772588 PubMed DOI

Drastichova Z., Bourova L., Hejnova L., Jedelsky P., Svoboda P., Novotny J. (2010). Protein alterations induced by long-term agonist treatment of HEK293 cells expressing thyrotropin-releasing hormone receptor and G(11)alpha protein. J. Cell. Biochem. 109 (1), 255–264. 10.1002/jcb.22409 PubMed DOI

Drastichova Z., Novotny J. (2012a). Identification and subcellular localization of molecular complexes of G(q/11) protein in HEK293 cells. Acta Biochim. Biophys. Sin. 44 (8), 641–649. 10.1093/abbs/gms050 PubMed DOI

Drastichova Z., Novotny J. (2012b). Identification of a preassembled TRH receptor-G(q/11) protein complex in HEK293 cells. Cell Struct. Funct. 37 (1), 1–12. 10.1247/csf.11024 PubMed DOI

Drastichova Z., Trubacova R., Novotny J. (2022). β-Arrestin2 is critically involved in the differential regulation of phosphosignaling pathways by thyrotropin-releasing hormone and taltirelin. Cells 11, 1473. 10.3390/cells11091473 PubMed DOI PMC

Drmota T., Gould G. W., Milligan G. (1998a). Real time visualization of agonist-mediated redistribution and internalization of a green fluorescent protein-tagged form of the thyrotropin-releasing hormone receptor. J. Biol. Chem. 273 (37), 24000–24008. 10.1074/jbc.273.37.24000 PubMed DOI

Drmota T., Milligan G. (2000). Kinetic analysis of the internalization and recycling of [3H]TRH and C-terminal truncations of the long isoform of the rat thyrotropin-releasing hormone receptor-1.. Biochem. J. 346 (3), 711–718. 10.1042/bj3460711 PubMed DOI PMC

Drmota T., Novotny J., Gould G. W., Svoboda P., Milligan G. (1999). Visualization of distinct patterns of subcellular redistribution of the thyrotropin-releasing hormone receptor-1 and Gqα/G11α induced by agonist stimulation. Biochem. J. 340 (2), 529–538. 10.1042/bj3400529 PubMed DOI PMC

Drmota T., Novotny J., Kim G. D., Eidne K. A., Milligan G., Svoboda P. (1998b). Agonist-induced internalization of the G protein G(11)alpha and thyrotropin-releasing hormone receptors proceed on different time scales. J. Biol. Chem. 273 (34), 21699–21707. 10.1074/jbc.273.34.21699 PubMed DOI

Du D. Y., Raaka B. M., Grimberg H., Lupu-Meiri M., Oron Y., Gershengorn M. C. (2005). Carboxyl tail cysteine mutants of the thyrotropin-releasing hormone receptor type 1 exhibit constitutive signaling: Role of palmitoylation. Mol. Pharmacol. 68 (1), 204–209. 10.1124/mol.105.012641 PubMed DOI

Duthie S. M., Taylor P. L., Anderson L., Cook J., Eidne K. A. (1993). Cloning and functional characterisation of the human TRH receptor. Mol. Cell. Endocrinol. 95 (1-2), R11–R15. 10.1016/0303-7207(93)90043-j PubMed DOI

Duval F., Mokrani M. C., Erb A., Danila V., Lopera F. G., Foucher J. R., et al. (2021). Thyroid axis activity and dopamine function in depression. Psychoneuroendocrinology 128, 105219. 10.1016/j.psyneuen.2021.105219 PubMed DOI

Engel S., Gershengorn M. C. (2007). Thyrotropin-releasing hormone and its receptors--a hypothesis for binding and receptor activation. Pharmacol. Ther. 113 (2), 410–419. 10.1016/j.pharmthera.2006.09.004 PubMed DOI

Faccenda E., Melmed S., Bevan J. S., Eidne K. A. (1996). Structure of the thyrotrophin-releasing hormone receptor in human pituitary adenomas. Clin. Endocrinol. (Oxf). 44 (3), 341–347. 10.1046/j.1365-2265.1996.684506.x PubMed DOI

Faden A. I., Knoblach S. M., Movsesyan V. A., Lea P. M., Cernak I. (2005a). Novel neuroprotective tripeptides and dipeptides. Ann. N. Y. Acad. Sci. 1053, 472–481. 10.1111/j.1749-6632.2005.tb00057.x PubMed DOI

Faden A. I., Movsesyan V. A., Knoblach S. M., Ahmed F., Cernak B. (2005b). Neuroprotective effects of novel small peptides in vitro and after brain injury. Neuropharmacology 49 (3), 410–424. 10.1016/j.neuropharm.2005.04.001 PubMed DOI

Franco R., Aguinaga D., Jiménez J., Lillo J., Martínez-Pinilla E., Navarro G. (2018). Biased receptor functionality versus biased agonism in G-protein-coupled receptors. Biomol. Concepts 9 (1), 143–154. 10.1515/bmc-2018-0013 PubMed DOI

Freeman M. E., Kanyicska B., Lerant A., Nagy G. (2000). Prolactin: structure, function, and regulation of secretion. Physiol. Rev. 80 (4), 1523–1631. 10.1152/physrev.2000.80.4.1523 PubMed DOI

Fröhlich E., Wahl R. (2019). The forgotten effects of thyrotropin-releasing hormone: Metabolic functions and medical applications. Front. Neuroendocrinol. 52, 29–43. 10.1016/j.yfrne.2018.06.006 PubMed DOI

Fukami M., Suzuki E., Igarashi M., Miyado M., Ogata T. (2018). Gain-of-function mutations in G-protein-coupled receptor genes associated with human endocrine disorders. Clin. Endocrinol. 88 (3), 351–359. 10.1111/cen.13496 PubMed DOI

Galas L., Raoult E., Tonon M. C., Okada R., Jenks B. G., Castaño J. P., et al. (2009). TRH acts as a multifunctional hypophysiotropic factor in vertebrates. Gen. Comp. Endocrinol. 164 (1), 40–50. 10.1016/j.ygcen.2009.05.003 PubMed DOI

García M., González de Buitrago J., Jiménez-Rosés M., Pardo L., Hinkle P. M., Moreno J. C. (2017). Central hypothyroidism due to a TRHR mutation causing impaired ligand affinity and transactivation of Gq. J. Clin. Endocrinol. Metab. 102 (7), 2433–2442. 10.1210/jc.2016-3977 PubMed DOI PMC

Gary K. A., Sevarino K. A., Yarbrough G. G., Prange A. J., Winokur A. (2003). The thyrotropin-releasing hormone (TRH) hypothesis of homeostatic regulation: implications for TRH-based therapeutics. J. Pharmacol. Exp. Ther. 305 (2), 410–416. 10.1124/jpet.102.044040 PubMed DOI

Gautvik K. M., Walaas E., Walaas O. (1977). Effect of thyroliberin on the concentration of adenosine 3':5'-phosphate and on the activity of adenosine 3':5'-phosphate-dependent protein kinase in prolactin-producing cells in culture. Biochem. J. 162 (2), 379–386. 10.1042/bj1620379 PubMed DOI PMC

Gehret A. U., Hinkle P. M. (2010). Importance of regions outside the cytoplasmic tail of G-protein-coupled receptors for phosphorylation and dephosphorylation. Biochem. J. 428 (2), 235–245. 10.1042/BJ20100139 PubMed DOI PMC

Gehret A. U., Jones B. W., Tran P. N., Cook L. B., Greuber E. K., Hinkle P. M. (2010). Role of helix 8 of the thyrotropin-releasing hormone receptor in phosphorylation by G protein-coupled receptor kinase. Mol. Pharmacol. 77 (2), 288–297. 10.1124/mol.109.059733 PubMed DOI PMC

Gershengorn M. C., Osman R. (1996). Molecular and cellular biology of thyrotropin-releasing hormone receptors. Physiol. Rev. 76 (1), 175–191. 10.1152/physrev.1996.76.1.175 PubMed DOI

Gollasch M., Kleuss C., Hescheler J., Wittig B., Schultz G. (1993). G(I2) and protein-kinase-C are required for thyrotropin-releasing hormone-induced stimulation of voltage-dependent Ca2+ channels in rat pituitary GH3 cells. Proc. Natl. Acad. Sci. U. S. A. 90 (13), 6265–6269. 10.1073/pnas.90.13.6265 PubMed DOI PMC

Gordeladze J. O., Bjoro T., Ostberg B. C., Sand O., Torjesen P., Haug E., et al. (1988). Phorbol esters and thyroliberin have distinct actions regarding stimulation of prolactin secretion and activation of adenylate cyclase in rat pituitary tumour cells (GH4C1 cells).. Biochem. Pharmacol. 37 (16), 3133–3138. 10.1016/0006-2952(88)90311-5 PubMed DOI

Grimberg H., Zaltsman I., Lupu-Meiri M., Gershengorn M. C., Oron Y. (1999). Inverse agonist abolishes desensitization of a constitutively active mutant of thyrotropin-releasing hormone receptor: role of cellular calcium and protein kinase C. Br. J. Pharmacol. 126 (5), 1097–1106. 10.1038/sj.bjp.0702415 PubMed DOI PMC

Groarke D. A., Drmota T., Bahia D. S., Evans N. A., Wilson S., Milligan G. (2001). Analysis of the C-terminal tail of the rat thyrotropin-releasing hormone receptor-1 in interactions and cointernalization with beta-arrestin 1-green fluorescent protein. Mol. Pharmacol. 59 (2), 375–385. 10.1124/mol.59.2.375 PubMed DOI

Gutierrez-Mariscal M., de Gortari P., Lopez-Rubalcava C., Martinez A., Joseph-Bravo P. (2008). Analysis of the anxiolytic-like effect of TRH and the response of amygdalar TRHergic neurons in anxiety. Psychoneuroendocrinology 33 (2), 198–213. 10.1016/j.psyneuen.2007.11.002 PubMed DOI

Han B. M., Tashjian A. H. (1995a). Identification of Asn289 as a ligand binding site in the rat thyrotropin-releasing hormone (THR) receptor as determined by complementary modifications in the ligand and receptor: a new model for THR binding. Biochemistry 34 (41), 13412–13422. 10.1021/bi00041a019 PubMed DOI

Han B. M., Tashjian A. H. (1995b). Importance of extracellular domains for ligand-binding in the thyrotropin-releasing-hormone receptor. Mol. Endocrinol. 9 (12), 1708–1719. 10.1210/mend.9.12.8614407 PubMed DOI

Hanyaloglu A. C., Seeber R. M., Kohout T. A., Lefkowitz R. J., Eidne K. A. (2002). Homo- and hetero-oligomerization of thyrotropin-releasing hormone (TRH) receptor subtypes - differential regulation of beta-arrestins 1 and 2. J. Biol. Chem. 277 (52), 50422–50430. 10.1074/jbc.M209340200 PubMed DOI

Hanyaloglu A. C., Vrecl M., Kroeger K. M., Miles L. E., Qian H., Thomas W. G., et al. (2001). 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. 276 (21), 18066–18074. 10.1074/jbc.M009275200 PubMed DOI

Hara J., Gerashchenko D., Wisor J. P., Sakurai T., Xie X. M., Kilduff T. S. (2009). Thyrotropin-releasing hormone increases behavioral arousal through modulation of hypocretin/orexin neurons. J. Neurosci. 29 (12), 3705–3714. 10.1523/JNEUROSCI.0431-09.2009 PubMed DOI PMC

Harder S., Dammann O., Buck F., Zwiers H., Lederis K., Richter D., et al. (2001a). Cloning of two thyrotropin-releasing hormone receptor subtypes from a lower vertebrate (Catostomus commersoni): Functional expression, gene structure, and evolution. Gen. Comp. Endocrinol. 124 (2), 236–245. 10.1006/gcen.2001.7709 PubMed DOI

Harder S., Lu X. P., Wang W., Buck F., Gershengorn M. C., Bruhn T. O. (2001b). 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), 1188–1194. 10.1210/endo.142.3.8019 PubMed DOI

Harvey S. (1990). Thyrotrophin-releasing hormone: a growth hormone-releasing factor. J. Endocrinol. 125 (3), 345–358. 10.1677/joe.0.1250345 PubMed DOI

Hashimoto T., Fukuda N. (1990). Effect of thyrotropin-releasing hormone on the time course of neurologic recovery after spinal cord injury in the rat. Jpn. J. Pharmacol. 53 (4), 479–486. 10.1254/jjp.53.479 PubMed DOI

Hawley R. J., Kratz R., Goodman R. R., McCutchen C. B., Sirdofsky M., Hanson P. A. (1987). Treatment of amyotrophic lateral sclerosis with the TRH analog DN-1417. Neurology 37 (4), 715–717. 10.1212/wnl.37.4.715 PubMed DOI

Heximer S. P., Watson N., Linder M. E., Blumer K. J., Hepler J. R. (1997). RGS2/G0S8 is a selective inhibitor of Gqalpha function. Proc. Natl. Acad. Sci. U. S. A. 94 (26), 14389–14393. 10.1073/pnas.94.26.14389 PubMed DOI PMC

Hinkle P. M., Gehret A. U., Jones B. W. (2012). Desensitization, trafficking, and resensitization of the pituitary thyrotropin-releasing hormone receptor. Front. Neurosci. 6, 180. 10.3389/fnins.2012.00180 PubMed DOI PMC

Hinkle P. M., Tashjian A. H. (1977). Adenylyl cyclase and cyclic nucleotide phosphodiesterases in GH-strains of rat pituitary cells. Endocrinology 100 (4), 934–944. 10.1210/endo-100-4-934 PubMed DOI

Hoermann R., Midgley J. E., Larisch R., Dietrich J. W. (2015). Homeostatic control of the thyroid-pituitary Axis: Perspectives for diagnosis and treatment. Front. Endocrinol. (Lausanne) 6, 177. 10.3389/fendo.2015.00177 PubMed DOI PMC

Ijiro T., Yaguchi A., Yokoyama A., Kiguchi S. (2022). Rovatirelin ameliorates motor dysfunction in the cytosine arabinoside-induced rat model of spinocerebellar degeneration via acetylcholine and dopamine neurotransmission. Clin. Exp. Pharmacol. Physiol. 49 (9), 950–958. 10.1111/1440-1681.13675 PubMed DOI

Janovick J. A., Spicer T. P., Bannister T. D., Scampavia L., Conn P. M. (2017). Pharmacoperone rescue of vasopressin 2 receptor mutants reveals unexpected constitutive activity and coupling bias. PLoS ONE 12 (8), e0181830. 10.1371/journal.pone.0181830 PubMed DOI PMC

Jantas D., Jaworska-Feil L., Lipkowski A. W., Lason W. (2009). Effects of TRH and its analogues on primary cortical neuronal cell damage induced by various excitotoxic, necrotic and apoptotic agents. Neuropeptides 43 (5), 371–385. 10.1016/j.npep.2009.07.002 PubMed DOI

Jaworska-Feil L., Jantas D., Leskiewicz M., Budziszewska B., Kubera M., Basta-Kaim A., et al. (2010). Protective effects of TRH and its analogues against various cytotoxic agents in retinoic acid (RA)-differentiated human neuroblastoma SH-SY5Y cells. Neuropeptides 44 (6), 495–508. 10.1016/j.npep.2010.08.004 PubMed DOI

Jin H. K., Fedorowicz G., Yang R. H., Ogasawara A., Peale F., Pham T., et al. (2004). Thyrotropin-releasing hormone is induced in the left ventricle of rats with heart failure and can provide inotropic support to the failing heart. Circulation 109 (18), 2240–2245. 10.1161/01.CIR.0000127951.13380.B4 PubMed DOI

Johansen P. W., Lund H. W., Gordeladze J. O. (2001a). Specific combinations of G-protein subunits discriminate hormonal signalling in rat pituitary (GH(3)) cells in culture. Cell. Signal. 13 (4), 251–256. 10.1016/s0898-6568(01)00144-9 PubMed DOI

Johansen P. W., Paulssen R. H., Bjoro T., Gautvik K. M., Gordeladze J. O. (2001b). Distinct guanine nucleotide binding protein alpha-subunit receptor coupling in GH cell lines: Effects of bromocriptine and hormones on effector enzyme modulation. Cell. Physiol. biochem. 11 (6), 339–352. 10.1159/000047820 PubMed DOI

Jones B. W., Hinkle P. M. (2008). Arrestin binds to different phosphorylated regions of the thyrotropin-releasing hormone receptor with distinct functional consequences. Mol. Pharmacol. 74 (1), 195–202. 10.1124/mol.108.045948 PubMed DOI PMC

Jones B. W., Hinkle P. M. (2005). Beta-arrestin mediates desensitization and internalization but does not affect dephosphorylation of the thyrotropin-releasing hormone receptor. J. Biol. Chem. 280 (46), 38346–38354. 10.1074/jbc.M502918200 PubMed DOI

Jones B. W., Hinkle P. M. (2009). Subcellular trafficking of the TRH receptor: effect of phosphorylation. Mol. Endocrinol. 23 (9), 1466–1478. 10.1210/me.2009-0119 PubMed DOI PMC

Jones B. W., Song G. J., Greuber E. K., Hinkle P. M. (2007). Phosphorylation of the endogenous thyrotropin-releasing hormone receptor in pituitary GH3 cells and pituitary tissue revealed by phosphosite-specific antibodies. J. Biol. Chem. 282 (17), 12893–12906. 10.1074/jbc.M610854200 PubMed DOI

Joseph-Bravo P., Jaimes-Hoy L., Charli J. L. (2016). Advances in TRH signaling. Rev. Endocr. Metab. Disord. 17 (4), 545–558. 10.1007/s11154-016-9375-y PubMed DOI

Joseph-Bravo P., Jaimes-Hoy L., Uribe R. M., Charli J. L. (2015). 60 years of neuroendocrinology: TRH, the first hypophysiotropic releasing hormone isolated: control of the pituitary-thyroid axis. J. Endocrinol. 226 (2), T85–T100. 10.1530/JOE-15-0124 PubMed DOI

Jumper J., Evans R., Pritzel A., Green T., Figurnov M., Ronneberger O., et al. (2021). Highly accurate protein structure prediction with AlphaFold. Nature 596 (7873), 583–589. 10.1038/s41586-021-03819-2 PubMed DOI PMC

Kakarala K. K., Jamil K. (2014). Sequence-structure based phylogeny of GPCR Class A Rhodopsin receptors. Mol. Phylogenet. Evol. 74, 66–96. 10.1016/j.ympev.2014.01.022 PubMed DOI

Kamath J. (2012). Cancer-related fatigue, inflammation and thyrotropin-releasing hormone. Curr. Aging Sci. 5 (3), 195–202. 10.2174/1874609811205030005 PubMed DOI

Kanasaki H., Fukunaga K., Takahashi K., Miyazaki K., Miyamoto E. (2000). Involvement of p38 mitogen-activated protein kinase activation in bromocriptine-induced apoptosis in rat pituitary GH3 cells. Biol. Reprod. 62 (6), 1486–1494. 10.1095/biolreprod62.6.1486 PubMed DOI

Kanasaki H., Fukunaga K., Takahashi K., Miyazaki K., Miyamoto E. (1999). Mitogen-activated protein kinase activation by stimulation with thyrotropin-releasing hormone in rat pituitary GH3 cells. Biol. Reprod. 61 (1), 319–325. 10.1095/biolreprod61.1.319 PubMed DOI

Kanasaki H., Oride A., Mijiddorj T., Kyo S. (2015). Role of thyrotropin-releasing hormone in prolactin-producing cell models. Neuropeptides 54, 73–77. 10.1016/j.npep.2015.08.001 PubMed DOI

Kanda Y., Koike K., Ohmichi M., Sawada T., Hirota K., Miyake A. (1994). A possible involvement of tyrosine kinase in TRH-induced prolactin secretion in GH3 cells. Biochem. Biophys. Res. Commun. 199 (3), 1447–1452. 10.1006/bbrc.1994.1393 PubMed DOI

Kang J. H., Shi Y. F., Xiang B., Qu B., Su W. J., Zhu M., et al. (2005). A nuclear function of beta-arrestin1 in GPCR signaling: Regulation of histone acetylation and gene transcription. Cell 123 (5), 833–847. 10.1016/j.cell.2005.09.011 PubMed DOI

Kat o Z., Okuda M., Okumura Y., Arai T., Teramoto T., Nishimura M., et al. (2009). Oral administration of the thyrotropin-releasing hormone (TRH) analogue, taltireline hydrate, in spinal muscular atrophy. J. Child. Neurol. 24 (8), 1010–1012. 10.1177/0883073809333535 PubMed DOI

Kelly J. A., Boyle N. T., Cole N., Slator G. R., Colivicchi M. A., Stefanini C., et al. (2015). First-in-class thyrotropin-releasing hormone (TRH)-based compound binds to a pharmacologically distinct TRH receptor subtype in human brain and is effective in neurodegenerative models. Neuropharmacology 89, 193–203. 10.1016/j.neuropharm.2014.09.024 PubMed DOI

Kenakin T. (2011). Functional selectivity and biased receptor signaling. J. Pharmacol. Exp. Ther. 336 (2), 296–302. 10.1124/jpet.110.173948 PubMed DOI

Keshet Y., Seger R. (2010). The MAP kinase signaling cascades: A system of hundreds of components regulates a diverse array of physiological functions. Methods Mol. Biol. Clift. N.J.) 661, 3–38. 10.1007/978-1-60761-795-2_1 PubMed DOI

Kharkevich D. A., Chizh B. A., Kasparov S. A. (1991). Stimulant effect of thyrotropin-releasing hormone and its analog, RGH 2202, on the diaphragm respiratory activity, and their antagonism with morphine: possible involvement of the N-methyl-D-aspartate receptors. Brain Res. 551 (1-2), 110–115. 10.1016/0006-8993(91)90920-q PubMed DOI

Khomane K. S., Meena C. L., Jain R., Bansal A. K. (2011). Novel thyrotropin-releasing hormone analogs: a patent review. Expert Opin. Ther. Pat. 21 (11), 1673–1691. 10.1517/13543776.2011.623127 PubMed DOI

Khoury E., Nikolajev L., Simaan M., Namkung Y., Laporte S. A. (2014). Differential regulation of endosomal GPCR/β-arrestin complexes and trafficking by MAPK. J. Biol. Chem. 289 (34), 23302–23317. 10.1074/jbc.M114.568147 PubMed DOI PMC

Kim G. D., Carr I. C., Anderson L. A., Zabavnik J., Eidne K. A., Milligan G. (1994). The long isoform of the rat thyrotropin-releasing-hormone receptor down-regulates G(Q) proteins. J. Biol. Chem. 269 (31), 19933–19940. 10.1016/s0021-9258(17)32110-5 PubMed DOI

Kineman R. D., Gettys T. W., Frawley L. S. (1996). Role of guanine nucleotide-binding proteins, G(i alpha 3) and G(s alpha), in dopamine and thyrotropin-releasing hormone signal transduction: Evidence for competition and commonality. J. Endocrinol. 148 (3), 447–455. 10.1677/joe.0.1480447 PubMed DOI

Kinoshita K., Watanabe Y., Yamamura M., Matsuoka Y. (1998). TRH receptor agonists ameliorate 3-acetylpyridine-induced ataxia through NMDA receptors in rats. Eur. J. Pharmacol. 343 (2-3), 129–133. 10.1016/s0014-2999(97)01539-2 PubMed DOI

Komolov K. E., Benovic J. L. (2018). G protein-coupled receptor kinases: Past, present and future. Cell. Signal. 41, 17–24. 10.1016/j.cellsig.2017.07.004 PubMed DOI PMC

Koo K. B., Suh H. J., Ra K. S., Choi J. W. (2011). Protective effect of cyclo(his-pro) on streptozotocin-induced cytotoxicity and apoptosis in vitro . J. Microbiol. Biotechnol. 21 (2), 218–227. 10.4014/jmb.1012.12003 PubMed DOI

Koulouri O., Nicholas A. K., Schoenmakers E., Mokrosinski J., Lane F., Cole T., et al. (2016). A novel thyrotropin-releasing hormone receptor missense mutation (P81R) in central congenital hypothyroidism. J. Clin. Endocrinol. Metab. 101 (3), 847–851. 10.1210/jc.2015-3916 PubMed DOI PMC

Kroeger K. M., Hanyaloglu A. C., Seeber R. M., Miles L. E. C., Eidne K. A. (2001). Constitutive and agonist-dependent homo-oligomerization of the thyrotropin-releasing hormone receptor - detection in living cells using bioluminescence resonance energy transfer. J. Biol. Chem. 276 (16), 12736–12743. 10.1074/jbc.M011311200 PubMed DOI

Laakkonen L. J., Guarnieri F., Perlman J. H., Gershengorn M. C., Osman R. (1996). A refined model of the thyrotropin-releasing hormone (TRH) receptor binding pocket. Novel mixed mode Monte Carlo stochastic dynamics simulations of the complex between TRH and TRH receptor. Biochemistry 35 (24), 7651–7663. 10.1021/bi952203j PubMed DOI

Lee T. W., Anderson L. A., Eidne K. A., Milligan G. (1995). Comparison of the signalling properties of the long and short isoforms of the rat thyrotropin-releasing-hormone receptor following expression in rat 1 fibroblasts. Biochem. J. 310 (1), 291–298. 10.1042/bj3100291 PubMed DOI PMC

Lei Q., Talley E. M., Bayliss D. A. (2001). Receptor-mediated inhibition of G protein-coupled inwardly rectifying potassium channels involves G(alpha)q family subunits, phospholipase C, and a readily diffusible messenger. J. Biol. Chem. 276 (20), 16720–16730. 10.1074/jbc.M100207200 PubMed DOI

Li X. X., Li Z. Y., Deng Y., Zhang J. N., Li J., Wang Y. J. (2020). Characterization of a novel thyrotropin-releasing hormone receptor, TRHR3, in chickens. Poult. Sci. 99 (3), 1643–1654. 10.1016/j.psj.2019.10.062 PubMed DOI PMC

Liu W. Y., Liu H., Aggarwal J., Huang Z. L., Horner R. L. (2020). Differential activating effects of thyrotropin-releasing hormone and its analog taltirelin on motor output to the tongue musculature in vivo . Sleep 43 (9), zsaa053. Sleep. 10.1093/sleep/zsaa053 PubMed DOI PMC

López-Barneo J., Castellano A., Toledo-Aral J. (1990). Thyrotropin-releasing-hormone (TRH) and its physiological metabolite TRH-OH inhibit Na+ channel activity in mammalian septal neurons. Proc. Natl. Acad. Sci. U. S. A. 87 (20), 8150–8154. 10.1073/pnas.87.20.8150 PubMed DOI PMC

Luo L., Luo J. Z., Jackson I. (2013). Tripeptide amide L-pyroglutamyl-histidyl-L-prolineamide (L-PHP-thyrotropin-releasing hormone, TRH) promotes insulin-producing cell proliferation. Curr. Aging Sci. 6 (1), 8–13. 10.2174/1874609811306010002 PubMed DOI

Luo L., Stopa E. G. (2004). Thyrotropin releasing hormone inhibits tau phosphorylation by dual signaling pathways in hippocampal neurons. J. Alzheimers Dis. 6 (5), 527–536. 10.3233/jad-2004-6510 PubMed DOI

Luo L., Yano N. (2005). Thyrotropin releasing hormone (TRH) affects gene expression in pancreatic beta-cells. Endocr. Res. 31 (3), 185–198. 10.1080/07435800500371763 PubMed DOI

Luttrell L. M., Ferguson S. S. G., Daaka Y., Miller W. E., Maudsley S., Della Rocca G. J., et al. (1999). beta-arrestin-dependent formation of beta(2) adrenergic receptor Src protein kinase complexes. Science 283 (5402), 655–661. 10.1126/science.283.5402.655 PubMed DOI

Luttrell L. M., Roudabush F. L., Choy E. W., Miller W. E., Field M. E., Pierce K. L., et al. (2001). Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Proc. Natl. Acad. Sci. U. S. A. 98 (5), 2449–2454. 10.1073/pnas.041604898 PubMed DOI PMC

Mancini A. D., Bertrand G., Vivot K., Carpentier É., Tremblay C., Ghislain J., et al. (2015). β-Arrestin recruitment and biased agonism at free fatty acid receptor 1. J. Biol. Chem. 290 (34), 21131–21140. 10.1074/jbc.M115.644450 PubMed DOI PMC

Marangell L. B., George M. S., Callahan A. M., Ketter T. A., Pazzaglia P. J., L'Herrou T. A., et al. (1997). Effects of intrathecal thyrotropin-releasing hormone (protirelin) in refractory depressed patients. Arch. Gen. Psychiatry 54 (3), 214–222. 10.1001/archpsyc.1997.01830150034007 PubMed DOI

Mariggio S., Garcia-Hoz C., Sarnago S., De Blasi A., Mayor F., Ribas C. (2006). Tyrosine phosphorylation of G-protein-coupled-receptor kinase 2 (GRK2) by c-Src modulates its interaction with Galphaq. Cell. Signal. 18 (11), 2004–2012. 10.1016/j.cellsig.2006.03.004 PubMed DOI

Mekuchi M., Saito Y., Aoki Y., Masud a. T., Iigo M., Yanagisawa T. (2011). Molecular cloning, gene structure, molecular evolution and expression analyses of thyrotropin-releasing hormone receptors from medaka (Oryzias latipes). Gen. Comp. Endocrinol. 170 (2), 374–380. 10.1016/j.ygcen.2010.10.013 PubMed DOI

Mellado M., Fernández-Agulló T., Rodríguez-Frade J. M., San Frutos M. G., de la Peña P., Martínez-A , C., et al. (1999). Expression analysis of the thyrotropin-releasing hormone receptor (TRHR) in the immune system using agonist anti-TRHR monoclonal antibodies. FEBS Lett. 451 (3), 308–314. 10.1016/s0014-5793(99)00607-9 PubMed DOI

Minakhina S., Bansal S., Zhang A., Brotherton M., Janodia R., De Oliveira V., et al. (2020). A direct comparison of thyroid hormone receptor protein levels in mice provides unexpected insights into thyroid hormone action. Thyroid 30 (8), 1193–1204. 10.1089/thy.2019.0763 PubMed DOI PMC

Miranda P., Giraldez T., de la Pena P., Manso D. G., Alonso-Ron C., Gomez-Varela D., et al. (2005). Specificity of TRH receptor coupling to G-proteins for regulation of ERG K+ channels in GH(3) rat anterior pituitary cells. J. Physiol. Lond. 566 (3), 717–736. 10.1113/jphysiol.2005.085803 PubMed DOI PMC

Mohammadi S., Dolatshahi M., Rahmani F. (2021). Shedding light on thyroid hormone disorders and Parkinson disease pathology: mechanisms and risk factors. J. Endocrinol. Invest. 44 (1), 1–13. 10.1007/s40618-020-01314-5 PubMed DOI

Molchan S. E., Mellow A. M., Lawlor B. A., Weingartner H. J., Cohen R. M., Cohen M. R., et al. (1990). TRH attenuates scopolamine-induced memory impairment in humans. Psychopharmacology 100 (1), 84–89. 10.1007/BF02245795 PubMed DOI

Monga V., Meena C. L., Kaur N., Jain R. (2008). Chemistry and biology of thyrotropin-releasing hormone (TRH) and its analogs. Curr. Med. Chem. 15 (26), 2718–2733. 10.2174/092986708786242912 PubMed DOI

Moravcova R., Melkes B., Novotny J. (2018). TRH receptor mobility in the plasma membrane is strongly affected by agonist binding and by interaction with some cognate signaling proteins. J. Recept. Signal Transduct. Res. 38 (1), 20–26. 10.1080/10799893.2017.1398756 PubMed DOI

Mulla C. M., Geras-Raaka E., Raaka B. M., Gershengorn M. C. (2009). High levels of thyrotropin-releasing hormone receptors activate programmed cell death in human pancreatic precursors. Pancreas 38 (2), 197–202. 10.1097/MPA.0b013e31818d14a8 PubMed DOI PMC

Nelson E. J., Hinkle P. M. (1994a). Characteristics of the Ca2+ spike and oscillations induced by different doses of thyrotropin-releasing hormone (TRH) in individual pituitary cells and nonexcitable cells transfected with TRH receptor complementary deoxyribonucleic acid. Endocrinology 135 (3), 1084–1092. 10.1210/endo.135.3.8070350 PubMed DOI

Nelson E. J., Hinkle P. M. (1994b). Thyrotropin-releasing hormone activates Ca2+ efflux. Evidence suggesting that a plasma membrane Ca2+ pump is an effector for a G-protein-coupled Ca(2+)-mobilizing receptor. J. Biol. Chem. 269 (49), 30854–30860. 10.1016/s0021-9258(18)47360-7 PubMed DOI

Nillni E. A. (2010). Regulation of the hypothalamic thyrotropin releasing hormone (TRH) neuron by neuronal and peripheral inputs. Front. Neuroendocrinol. 31 (2), 134–156. 10.1016/j.yfrne.2010.01.001 PubMed DOI PMC

Novotny J., Krusek J., Drmota T., Svoboda P. (1999). Overexpression of the G protein G(11)alpha prevents desensitization of Ca2+ response to thyrotropin-releasing hormone. Life Sci. 65 (9), 889–900. 10.1016/s0024-3205(99)00319-7 PubMed DOI

Núñez L., Bird G. S., Hernando-Pérez E., Pérez-Riesgo E., Putney J. W., Jr, Villalobos C. (2019). Store-operated Ca2+ entry and Ca2+ responses to hypothalamic releasing hormones in anterior pituitary cells from Orai1-/- and heptaTRPC knockout mice. Biochim. Biophys. Acta. Mol. Cell Res. 1866 (7), 1124–1136. 10.1016/j.bbamcr.2018.11.006 PubMed DOI PMC

Nussenzveig D. R., Heinflink M., Gershengorn M. C. (1993a). Agonist-stimulated internalization of the thyrotropin-releasing hormone receptor is dependent on two domains in the receptor carboxyl terminus. J. Biol. Chem. 268 (4), 2389–2392. 10.1016/s0021-9258(18)53788-1 PubMed DOI

Nussenzveig D. R., Heinflink M., Gershengorn M. C. (1993b). Decreased levels of internalized thyrotropin-releasing-hormone receptors after uncoupling from guanine-nucleotide-binding protein and phospholipase-C. Mol. Endocrinol. 7 (9), 1105–1111. 10.1210/mend.7.9.8247012 PubMed DOI

O'Dowd B. F., Lee D. K., Huang W., Nguyen T., Cheng R. G., Liu Y., et al. (2000). TRH-R2 exhibits similar binding and acute signaling but distinct regulation and anatomic distribution compared with TRH-R1. Mol. Endocrinol. 14 (1), 183–193. 10.1210/mend.14.1.0407 PubMed DOI

Ohbu S., Yoshioka N., Honda M., Andoh Y., Sato Y., Takao N., et al. (1995). TRH stimulation test in healthy elderly - paradoxical response of growth-hormone is abnormal in normal aging. Intern. Med. 34 (3), 148–152. 10.2169/internalmedicine.34.148 PubMed DOI

Ohmichi M., Koike K., Nohara A., Kanda Y., Sakamoto T., Zhang Z. X., et al. (1994a). Dopamine inhibits trh-induced MAP kinase activation in dispersed rat anterior-pituitary-cells. Biochem. Biophys. Res. Commun. 201 (2), 642–648. 10.1006/bbrc.1994.1749 PubMed DOI

Ohmichi M., Sawada T., Kanda Y., Koike K., Hirota K., Miyake A., et al. (1994b). Thyrotropin-releasing-hormone stimulates MAP kinase-activity in GH3 cells by divergent pathways - evidence of a role for early tyrosine phosphorylation. J. Biol. Chem. 269 (5), 3783–3788. 10.1016/s0021-9258(17)41928-4 PubMed DOI

Ostasov P., Bourova L., Hejnova L., Novotny J., Svoboda P. (2007). Disruption of the plasma membrane integrity by cholesterol depletion impairs effectiveness of TRH receptor-mediated signal transduction via G(q)/G(11)alpha proteins. J. Recept. Signal Transduct. Res. 27 (5-6), 335–352. 10.1080/10799890701684142 PubMed DOI

Ostasov P., Krusek J., Durchankova D., Svoboda P., Novotny J. (2008). Ca2+ responses to thyrotropin-releasing hormone and angiotensin II: the role of plasma membrane integrity and effect of G(11)alpha protein overexpression on homologous and heterologous desensitization. Cell biochem. Funct. 26 (2), 264–274. 10.1002/cbf.1453 PubMed DOI

Palomero T., Barros F., del Camino D., Viloria C. G., de la Pena P. (1998). A G protein beta gamma dimer-mediated pathway contributes to mitogen-activated protein kinase activation by thyrotropin-releasing hormone receptors in transfected COS-7 cells. Mol. Pharmacol. 53 (4), 613–622. 10.1124/mol.53.4.613 PubMed DOI

Paradis J. S., Ly S., Blondel-Tepaz E., Galan J. A., Beautrait A., Scott M. G. H., et al. (2015). Receptor sequestration in response to beta-arrestin-2 phosphorylation by ERK1/2 governs steady-state levels of GPCR cell-surface expression. Proc. Natl. Acad. Sci. U. S. A. 112 (37), E5160–E5168. 10.1073/pnas.1508836112 PubMed DOI PMC

Parmentier R., Kolbaev S., Klyuch B. P., Vandael D., Lin J. S., Selbach O., et al. (2009). Excitation of histaminergic tuberomamillary neurons by thyrotropin-releasing hormone. J. Neurosci. 29 (14), 4471–4483. 10.1523/JNEUROSCI.2976-08.2009 PubMed DOI PMC

Patwardhan A., Cheng N., Trejo J. (2021). Post-translational modifications of G protein-coupled receptors control cellular signaling dynamics in space and time. Pharmacol. Rev. 73 (1), 120–151. 10.1124/pharmrev.120.000082 PubMed DOI PMC

Paulssen E. J., Paulssen R. H., Gautvik K. M., Gordeladze J. O. (1992a). Cross-talk between phospholipase-C and adenylyl cyclase involves regulation of G-protein levels in GH3 rat pituitary-cells. Cell. Signal. 4 (6), 747–755. 10.1016/0898-6568(92)90056-e PubMed DOI

Paulssen E. J., Paulssen R. H., Gautvik K. M., Gordeladze J. O. (1992b). Hypothalamic hormones modulate G protein levels and second messenger responsiveness in GH3 rat pituitary tumour cells. Biochem. Pharmacol. 44 (3), 471–477. 10.1016/0006-2952(92)90438-o PubMed DOI

Paulssen R. H., Paulssen E. J., Gautvik K. M., Gordeladze J. O. (1992c). The thyroliberin receptor interacts directly with a stimulatory guanine-nucleotide-binding protein in the activation of adenylyl cyclase in GH3 rat pituitary tumour cells. Evidence obtained by the use of antisense RNA inhibition and immunoblocking of the stimulatory guanine-nucleotide-binding protein. Eur. J. Biochem. 204 (1), 413–418. 10.1111/j.1432-1033.1992.tb16651.x PubMed DOI

Perlman J. H., Colson A. O., Wang W., Bence K., Osman R., Gershengorn M. C. (1997). Interactions between conserved residues in transmembrane helices 1, 2, and 7 of the thyrotropin-releasing hormone receptor. J. Biol. Chem. 272 (18), 11937–11942. 10.1074/jbc.272.18.11937 PubMed DOI

Perlman J. H., Laakkonen L. J., Guarnieri F., Osman R., Gershengorn M. C. (1996). A refined model of the thyrotropin-releasing hormone (TRH) receptor binding pocket. Experimental analysis and energy minimization of the complex between TRH and TRH receptor. Biochemistry 35 (24), 7643–7650. 10.1021/bi952202r PubMed DOI

Perlman J. H., Laakkonen L., Osman R., Gershengorn M. C. (1994a). A model of the thyrotropin-releasing hormone (TRH) receptor binding pocket. Evidence for a second direct interaction between transmembrane helix 3 and TRH. J. Biol. Chem. 269 (38), 23383–23386. 10.1016/s0021-9258(17)31524-7 PubMed DOI

Perlman J. H., Thaw C. N., Laakkonen L., Bowers C. Y., Osman R., Gershengorn M. C. (1994b). Hydrogen-bonding interaction of thyrotropin-releasing-hormone (TRH) with transmembrane tyrosine-106 of the TRH receptor. J. Biol. Chem. 269 (3), 1610–1613. 10.1016/s0021-9258(17)42069-2 PubMed DOI

Perlman J. H., Wang W., Nussenzveig D. R., Gershengorn M. C. (1995). A disulfide bond between conserved extracellular cysteines in the thyrotropin-releasing-hormone receptor is critical for binding. J. Biol. Chem. 270 (42), 24682–24685. 10.1074/jbc.270.42.24682 PubMed DOI

Pesanova Z., Novotny J., Cerny J., Milligan G., Svoboda P. (1999). Thyrotropin-releasing hormone-induced depletion of G(q)alpha/G(11)alpha proteins from detergent-insensitive membrane domains. FEBS Lett. 464 (1-2), 35–40. 10.1016/s0014-5793(99)01666-x PubMed DOI

Petrou C., Chen L. C., Tashjian A. H. (1997). A receptor-G protein coupling-independent step in the internalization of the thyrotropin-releasing hormone receptor. J. Biol. Chem. 272 (4), 2326–2333. 10.1074/jbc.272.4.2326 PubMed DOI

Petrou C., Tashjian A. H. (1998). The thyrotropin-releasing hormone-receptor complex and G11alpha are both internalised into clathrin-coated vesicles. Cell. Signal. 10 (8), 553–559. 10.1016/s0898-6568(97)00190-3 PubMed DOI

Pitts L. H., Ross A., Chase G. A., Faden A. I. (1995). Treatment with thyrotropin-releasing-hormone (TRH) in patients with traumatic spinal-cord injuries. J. Neurotrauma 12 (3), 235–243. 10.1089/neu.1995.12.235 PubMed DOI

Przewłocka B., Labuz D., Mika J., Lipkowski A., van Luijtelaar G., Coenen A., et al. (1997). Protective effects of TRH and its analogues in chemical and genetic models of seizures. Pol. J. Pharmacol. 49 (5), 373–378. PubMed

Rajput S. K., Krishnamoorthy S., Pawar C., Kaur N., Monga V., Meena C. L., et al. (2009). Antiepileptic potential and behavioral profile of L-pGlu-(2-propyl)-L-His-L-ProNH(2), a newer thyrotropin-releasing hormone analog. Epilepsy Behav. 14 (1), 48–53. 10.1016/j.yebeh.2008.10.006 PubMed DOI

Rojas A., Su J., Yang L., Lee M., Cui N., Zhang X., et al. (2008). Modulation of the heteromeric Kir4.1-Kir5.1 channel by multiple neurotransmitters via Galphaq-coupled receptors. J. Cell. Physiol. 214 (1), 84–95. 10.1002/jcp.21169 PubMed DOI PMC

Rojo-Ruiz J., Navas-Navarro P., Nuñez L., García-Sancho J., Alonso M. T. (2021). Imaging of endoplasmic reticulum Ca2+ in the intact pituitary gland of transgenic mice expressing a low affinity Ca2+ indicator. Front. Endocrinol. (Lausanne) 11, 615777. 10.3389/fendo.2020.615777 PubMed DOI PMC

Rosano L., Cianfrocca R., Tocci P., Spinella F., Di Castro V., Spadaro F., et al. (2013). β-arrestin-1 is a nuclear transcriptional regulator of endothelin-1-induced β-catenin signaling. Oncogene 32 (42), 5066–5077. 10.1038/onc.2012.527 PubMed DOI

Rudajev V., Novotny J., Hejnova L., Milligan G., Svoboda P. (2005). 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. 138 (2), 111–125. 10.1093/jb/mvi114 PubMed DOI

Sah N., Rajput S. K., Singh J. N., Meena C. L., Jain R., Sikdar S. K., et al. (2011). L-pGlu-(2-propyl)-L-His-L-ProNH₂ attenuates 4-aminopyridine-induced epileptiform activity and sodium current: a possible action of new thyrotropin-releasing hormone analog for its anticonvulsant potential. Neuroscience 199, 74–85. 10.1016/j.neuroscience.2011.10.008 PubMed DOI

Sallese M., Mariggio S., D'Urbano E., Iacovelli L., De Blasi A., De BlAsi A. (2000). Selective regulation of Gq signaling by G protein-coupled receptor kinase 2: Direct interaction of kinase N terminus with activated gαq. Mol. Pharmacol. 57 (4), 826–831. 10.1124/mol.57.4.826 PubMed DOI

Sanchez-Fernandez G., Cabezudo S., Garcia-Hoz C., Tobin A. B., Mayor F., Ribas C. (2013). ERK5 activation by gq-coupled muscarinic receptors is independent of receptor internalization and beta-arrestin recruitment. PLoS ONE 8 (12), e84174. 10.1371/journal.pone.0084174 PubMed DOI PMC

Shibata A., Matano F., Fujiki Y., Mizunari T., Murai Y., Yokota H., et al. (2019). Efficacy of thyrotropin-releasing hormone analog for protracted disturbance of consciousness due to aneurysmal subarachnoid hemorrhage. J. Stroke Cerebrovasc. Dis. 28 (4), 988–993. 10.1016/j.jstrokecerebrovasdis.2018.12.036 PubMed DOI

Shimizu T., Tsutsumi R., Shimizu K., Tominaga N., Nagai M., Ugawa Y., et al. (2020). Differential effects of thyrotropin releasing hormone (TRH) on motor execution and motor adaptation process in patients with spinocerebellar degeneration. J. Neurol. Sci. 415, 116927. 10.1016/j.jns.2020.116927 PubMed DOI

Smith J. S., Lefkowitz R. J., Rajagopal S. (2018). Biased signalling: from simple switches to allosteric microprocessors. Nat. Rev. Drug Discov. 17 (4), 243–260. 10.1038/nrd.2017.229 PubMed DOI PMC

Smith J., Yu R., Hinkle P. M. (2001). Activation of MAPK by TRH requires clathrin-dependent endocytosis and PKC but not receptor interaction with beta-arrestin or receptor endocytosis. Mol. Endocrinol. 15 (9), 1539–1548. 10.1210/mend.15.9.0695 PubMed DOI

Song G. J., Hinkle P. M. (2005). Regulated dimerization of the thyrotropin releasing hormone receptor affects receptor trafficking but not signaling. Mol. Endocrinol. 19 (11), 2859–2870. 10.1210/me.2005-0133 PubMed DOI

Song G. J., Jones B. W., Hinkle P. M. (2007). Dimerization of the thyrotropin-releasing hormone receptor potentiates hormone-dependent receptor phosphorylation. Proc. Natl. Acad. Sci. U. S. A. 104 (46), 18303–18308. 10.1073/pnas.0702857104 PubMed DOI PMC

Sosa L., Gutiérrez S., Petiti J. P., Palmeri C. M., Mascanfroni I. D., Soaje M., et al. (2012). 17β-Estradiol modulates the prolactin secretion induced by TRH through membrane estrogen receptors via PI3K/Akt in female rat anterior pituitary cell culture. Am. J. Physiol. Endocrinol. Metab. 302 (10), E1189–E1197. 10.1152/ajpendo.00408.2011 PubMed DOI

Sterne-Marr R., Tesmer J. J. G., Day P. W., Stracquatanio R. P., Cilente J. A. E., O'Connor K. E., et al. (2003). G protein-coupled receptor Kinase 2/G alpha q/11 interaction. A novel surface on a regulator of G protein signaling homology domain for binding G alpha subunits. J. Biol. Chem. 278 (8), 6050–6058. 10.1074/jbc.M208787200 PubMed DOI

Stewart A., Fisher R. A. (2015). Introduction: G protein-coupled receptors and RGS proteins. Prog. Mol. Biol. Transl. Sci. 133, 1–11. 10.1016/bs.pmbts.2015.03.002 PubMed DOI

Storey N. M., O'Bryan J. P., Armstrong D. L. (2002). Rac and Rho mediate opposing hormonal regulation of the ether-a-go-go-related potassium channel. Curr. Biol. 12 (1), 27–33. 10.1016/s0960-9822(01)00625-x PubMed DOI

Straub R. E., Frech G. C., Joho R. H., Gershengorn M. C. (1990). Expression cloning of a cDNA encoding the mouse pituitary thyrotropin-releasing hormone receptor. Proc. Natl. Acad. Sci. U. S. A. 87 (24), 9514–9518. 10.1073/pnas.87.24.9514 PubMed DOI PMC

Sun Y. H., Zupan B., Raaka B. M., Toth M., Gershengorn M. C. (2009). TRH-Receptor-Type-2-Deficient mice are euthyroid and exhibit increased depression and reduced anxiety phenotypes. Neuropsychopharmacology 34 (6), 1601–1608. 10.1038/npp.2008.217 PubMed DOI PMC

Sun Y., Lu X., Gershengorn M. C. (2003). Thyrotropin-releasing hormone receptors -- similarities and differences. J. Mol. Endocrinol. 30 (2), 87–97. 10.1677/jme.0.0300087 PubMed DOI

Svoboda P., Kim G. D., Grassie M. A., Eidne K. A., Milligan G. (1996). Thyrotropin-releasing hormone-induced subcellular redistribution and down-regulation of G11alpha: analysis of agonist regulation of coexpressed G11alpha species variants. Mol. Pharmacol. 49 (4), 646–655. PubMed

Taché Y., Yoneda M. (1993). Central action of TRH to induce vagally mediated gastric cytoprotection and ulcer formation in rats. J. Clin. Gastroenterol. 17 (1), S58–S63. 10.1097/00004836-199312001-00013 PubMed DOI

Tanaka C., Maegaki Y., Koeda T., Ohta S., Takeshita K. (1998). Successful treatment of progressive myoclonus epilepsy with TRH. Pediatr. Neurol. 18 (5), 442–444. 10.1016/s0887-8994(97)00230-0 PubMed DOI

Teixeira L. B., Parreiras-E-Silva L. T., Bruder-Nascimento T., Duarte D. A., Simoes S. C., Costa R. M., et al. (2017). Ang-(1-7) is an endogenous beta-arrestin-biased agonist of the AT(1) receptor with protective action in cardiac hypertrophy. Sci. Rep. 7 (1), 11903. 10.1038/s41598-017-12074-3 PubMed DOI PMC

Thirunarayanan N., Nir E. A., Raaka B. M., Gershengorn M. C. (2013). Thyrotropin-releasing hormone receptor type 1 (TRH-R1), not TRH-R2, primarily mediates taltirelin actions in the CNS of mice. Neuropsychopharmacology 38 (6), 950–956. 10.1038/npp.2012.256 PubMed DOI PMC

Thirunarayanan N., Raaka B. M., Gershengorn M. C. (2012). Taltirelin is a superagonist at the human thyrotropin-releasing hormone receptor. Front. Endocrinol. (Lausanne) 3, 120. 10.3389/fendo.2012.00120 PubMed DOI PMC

Tian X., Kang D. S., Benovic J. L. (2014). β-arrestins and G protein-coupled receptor trafficking. Handb. Exp. Pharmacol. 219, 173–186. 10.1007/978-3-642-41199-1_9 PubMed DOI PMC

Tsuru J., Ishitobi Y., Ninomiya T., Kanehisa M., Imanaga J., Inoue A., et al. (2013). The thyrotropin-releasing hormone test may predict recurrence of clinical depression within ten years after discharge. Neuro Endocrinol. Lett. 34 (5), 409–417. PubMed

Varadi M., Anyango S., Deshpande M., Nair S., Natassia C., Yordanova G., et al. (2021). AlphaFold protein structure database: massively expanding the structural coverage of protein-sequence space with high-accuracy models. Nucleic Acids Res. 50 (D1), D439–D444. 10.1093/nar/gkab1061 PubMed DOI PMC

Veronesi M. C., Yard M., Jackson J., Lahiri D. K., Kubek M. J. (2007). An analog of thyrotropin-releasing hormone (TRH) is neuroprotective against glutamate-induced toxicity in fetal rat hippocampal neurons in vitro . Brain Res. 1128 (1), 79–85. 10.1016/j.brainres.2006.10.047 PubMed DOI PMC

Wang W., Gershengorn M. C. (1999). Rat TRH receptor type 2 exhibits higher basal signaling activity than TRH receptor type 1. Endocrinology 140 (10), 4916–4919. 10.1210/endo.140.10.7159 PubMed DOI

Wang Y. H., Jue S. F., Maurer R. A. (2000). Thyrotropin-releasing hormone stimulates phosphorylation of the epidermal growth factor receptor in GH(3) pituitary cells. Mol. Endocrinol. 14 (9), 1328–1337. 10.1210/mend.14.9.0512 PubMed DOI

Wang Y. H., Maurer R. A. (1999). A role for the mitogen-activated protein kinase in mediating the ability of thyrotropin-releasing hormone to stimulate the prolactin promoter. Mol. Endocrinol. 13 (7), 1094–1104. 10.1210/mend.13.7.0315 PubMed DOI

Watanave M., Matsuzaki Y., Nakajima Y., Ozawa A., Yamada M., Hirai H. (2018). Contribution of thyrotropin-releasing hormone to cerebellar long-term depression and motor learning. Front. Cell. Neurosci. 12, 490. 10.3389/fncel.2018.00490 PubMed DOI PMC

Yang F., Zhang H., Meng X., Li Y., Zhou Y., Ling S., et al. (2022). Structural insights into thyrotropin-releasing hormone receptor activation by an endogenous peptide agonist or its orally administered analogue. Cell Res. 0, 1–4. 10.1038/s41422-022-00646-6 PubMed DOI PMC

Yoneda M., Goto M., Nakamura K., Shimada T., Hiraishi H., Terano A., et al. (2005). Protective effect of central thyrotropin-releasing hormone analog on cerulein-induced acute pancreatitis in rats. Regul. Pept. 125 (1-3), 119–124. 10.1016/j.regpep.2004.08.015 PubMed DOI

Yoneda M., Sato Y., Nakamura K., Yokohama S., Kono T., Watanobe H., et al. (2003). Involvement of calcitonin gene-related peptide and capsaicin-sensitive afferents in central thyrotropin-releasing hormone-induced hepatic cytoprotection. Eur. J. Pharmacol. 478 (2-3), 173–177. 10.1016/j.ejphar.2003.08.040 PubMed DOI

Yu R., Hinkle P. M. (1999). Signal transduction and hormone-dependent internalization of the thyrotropin-releasing hormone receptor in cells lacking Gq and G11. J. Biol. Chem. 274 (22), 15745–15750. 10.1074/jbc.274.22.15745 PubMed DOI

Yu R., Hinkle P. M. (1998). Signal transduction, desensitization, and recovery of responses to thyrotropin-releasing hormone after inhibition of receptor internalization. Mol. Endocrinol. 12 (5), 737–749. 10.1210/mend.12.5.0110 PubMed DOI

Zaltsman I., Grimberg H., Lupu-Meiri M., Lifschitz L., Oron Y. (2000). Rapid desensitization of the TRH receptor and persistent desensitization of its constitutively active mutant. Br. J. Pharmacol. 130 (2), 315–320. 10.1038/sj.bjp.0703291 PubMed DOI PMC

Zarate A., Garcia I. C., Moran C., Fonseca M. E. (1986). Impaired glucose-tolerance coincides with abnormal release of growth-hormone following a glucose-load as well as in response to TRH in acromegaly. Horm. Metab. Res. 18 (6), 400–401. 10.1055/s-2007-1012326 PubMed DOI

Zarif H., Petit-Paitel A., Heurteaux C., Chabry J., Guyon A. (2016). TRH modulates glutamatergic synaptic inputs on CA1 neurons of the mouse hippocampus in a biphasic manner. Neuropharmacology 110, 69–81. 10.1016/j.neuropharm.2016.04.004 PubMed DOI

Zheng C., Chen G. Q., Tan Y., Zeng W. Q., Peng Q. W., Wang J., et al. (2018a). TRH analog, taltirelin improves motor function of hemi-PD rats without inducing dyskinesia via sustained dopamine stimulating effect. Front. Cell. Neurosci. 12, 417. 10.3389/fncel.2018.00417 PubMed DOI PMC

Zheng C., Chen G. Q., Tan Y., Zeng W. Q., Peng Q. W., Wang J., et al. (2018b). TRH analog, taltirelin protects dopaminergic neurons from neurotoxicity of MPTP and rotenone. Front. Cell. Neurosci. 12, 485. 10.3389/fncel.2018.00485 PubMed DOI PMC

Zhu C. C., Cook L. B., Hinkle P. M. (2002). Dimerization and phosphorylation of thyrotropin-releasing hormone receptors are modulated by agonist stimulation. J. Biol. Chem. 277 (31), 28228–28237. 10.1074/jbc.M204221200 PubMed DOI

Anorexigenic neuropeptides as anti-obesity and neuroprotective agents: exploring the neuroprotective effects of anorexigenic neuropeptides