Cloning and Characterization of a New Subtype of Thyrotropin-Releasing Hormone Receptors

Itadani, Hiraku; Nakamura, Toshio; Itoh, Junko; Iwaasa, Hisashi; Kanatani, Akio; Borkowski, Joseph A.; Ihara, Masaki; Ohta, Masataka

doi:10.1006/bbrc.1998.9268

Cited by 88 publications

(48 citation statements)

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“…There are two types of TRH receptors (TRHR1 and TRHR2) which have been identified previously (Straub et al 1990, Cao et al 1998, Itadani et al 1998. More recently, a third subtype of the receptor (TRHR3) has been cloned from Xenopus laevis (Bidaud et al 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Two subtypes of TRH cognate receptors have been identified. TRH receptor type 1 (TRHR1) was originally cloned in 1990 using expression cloning in Xenopus laevis (Straub et al 1990) and TRH receptor type 2 (TRHR2), which was identified in 1998 by two groups simultaneously (Cao et al 1998, Itadani et al 1998. Although TRHR1 and 2 share no more than 68% homology of their amino acid sequence, there are no significant differences in binding or in acute stimulation of signaling between the subtypes (O'Dowd et al 2000, Sun et al 2003.…”

Section: Introductionmentioning

confidence: 99%

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Expression of thyrotropin-releasing hormone receptor in immortalized beta-cell lines and rat pancreas

Luo

Yano²

2004

Journal of Endocrinology

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Thyrotropin-releasing hormone (TRH), a hypothalamic tripeptide, is expressed in pancreatic islets at peak levels during the late gestation and early neonate period. TRH increases insulin production in cultured -cells, suggesting that it might play a role in regulating pancreatic -cell function. However, there is limited information on TRH receptor expression in the pancreas. The aim of the present study was to explore the distribution of the TRH receptor in the pancreas and its function in pancreatic -cells. TRH receptor type 1 (TRHR1) gene expression was detected by RT-PCR and verified by Northern blotting and immunoblotting in the -cell lines, INS-1 and TC-6, and the rat pancreatic organ. The absence of TRH receptor type 2 expression in the tissue and cells indicated the tissue specificity of TRH receptor expression in the pancreas. The TRHR1 signals (detected by in situ hybridization) were distributed not only in islets but also in the surrounding areas of the pancreatic ductal and vasal epithelia. The apparent dissociation constant value for the affinity of [ 3 H]3-methyl-histidine TRH (MeTRH) is 4·19 in INS-1 and 3·09 nM in TC-6. In addition, TRH induced epidermal growth factor (EGF) receptor phosphorylation with a half-maximum concentration of approximately 50 nM, whereas the high affinity analogue of TRH, MeTRH, was 1 nM. This suggested that the affinity of TRH ligands for the TRH receptor influences the activation of EGF receptor phosphorylation in TC-6 cells. Our observations suggested that the biological role of TRH in pancreatic -cells is via the activation of TRHR1. Further research is required to identify the role of TRHR1 in the pancreas aside from the islets.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Expression of thyrotropin-releasing hormone receptor in immortalized beta-cell lines and rat pancreas

Luo

Yano²

2004

Journal of Endocrinology

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“…Two G Protein-Coupled Receptor (GPCR) subtypes, designated TRHR1 and TRHR2, have been identified to date in mediating TRH actions in non-human mammalian species (Cao et al, 1998;Itadani et al, 1998;Sun et al, 2003). Recent knock-out studies in mouse indicated that TRHR2 receptors account for no more that 5% of total binding in brain and that the CNS effects of TRH and TRH analogs were lost in mice in which TRHR1 was deleted (Thirunarayanan et al, 2013).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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

Kelly¹,

Boyle²,

Cole³

et al. 2015

Neuropharmacology

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Hardiman, O., 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 (2014), doi: 10.1016/j.neuropharm.2014.09.024. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPTABSTRACT JAK4D, a first-in-class thyrotropin-releasing hormone (TRH)-based compound, is a prospective therapeutic candidate offering a multifaceted approach to treating neurodegeneration and other CNS conditions. The purpose of these studies was to determine the ability of JAK4D to bind to TRH receptors in human brain and to evaluate its neuropharmacological effects in neurodegenerative animal models. Additionally, JAK4D brain permeation was examined in mouse, and initial toxicology was assessed in vivo and in vitro. We report that JAK4D bound selectively with nanomolar affinity to native TRH receptors in human hippocampal tissue and showed for the first time that these receptors are pharmacologically distinct from TRH receptors in human pituitary, thus revealing a new TRH receptor subtype which represents a promising neurotherapeutic target in human brain. Systemic administration of JAK4D elicited statistically significant and clinically-relevant neuroprotective effects in three established neurodegenerative animal models: JAK4D reduced cognitive deficits when administered post-insult in a kainate (KA)-induced rat model of neurodegeneration; it protected against free radical release and neuronal damage evoked by intrastriatal microdialysis of KA in rat; and it reduced motor decline, weight loss, and lumbar spinal cord neuronal loss in G93A-SOD1 transgenic Amyotrophic Lateral Sclerosis mice. Ability to cross the blood-brain-barrier and a clean initial toxicology profile were also shown. In light of these findings, JAK4D is an important tool for investigating the hitherto-unidentified central TRH receptor subtype reported herein and an attractive therapeutic candidate for neurodegenerative disorders.

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“…TRH is also known to have extrapituitary actions in the brain, spinal cord, cardiovascular, and gastrointestinal systems (10,11). The cloning of a second receptor for TRH (TRHR2) from rat brain and spinal cord provided a possible explanation for certain neurotransmitter actions of TRH, in particular the nociceptive and spinal cord regenerative actions (12)(13)(14). The two TRH receptor subtypes are ϳ50% homologous, and they exhibit similar binding affinities for TRH (12)(13)(14) and activate the same signaling pathways, although TRHR2 exhibits higher basal signaling activity (14 -16).…”

Section: G-protein-coupled Receptor (Gpcr)mentioning

confidence: 99%

“…The cloning of a second receptor for TRH (TRHR2) from rat brain and spinal cord provided a possible explanation for certain neurotransmitter actions of TRH, in particular the nociceptive and spinal cord regenerative actions (12)(13)(14). The two TRH receptor subtypes are ϳ50% homologous, and they exhibit similar binding affinities for TRH (12)(13)(14) and activate the same signaling pathways, although TRHR2 exhibits higher basal signaling activity (14 -16). TRHR1 and 2 are expressed in distinct compartments of the brain and spinal cord (12,14,17,18), although areas have been defined where both receptor subtypes are found (12,14).…”

Section: G-protein-coupled Receptor (Gpcr)mentioning

confidence: 99%

Homo- and Hetero-oligomerization of Thyrotropin-releasing Hormone (TRH) Receptor Subtypes

Hanyaloglu¹,

Seeber²,

Kohout³

et al. 2002

Journal of Biological Chemistry

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G-protein-coupled receptors (GPCRs) are regulated by a complex network of mechanisms such as oligomerization and internalization. Using the GPCR subtypes for thyrotropin-releasing hormone (TRHR1 and TRHR2), the aim of this study was to determine if subtype-specific differences exist in the trafficking process. If so, we wished to determine the impact of homo-and hetero-oligomerization on TRHR subtype trafficking as a potential mechanism for the differential cellular responses induced by TRH. Expression of either ␤-arrestin 1 or 2 promoted TRHR1 internalization. In contrast, only ␤-arrestin 2 could enhance TRHR2 internalization. The preference for ␤-arrestin 2 by TRHR2 was supported by the impairment of TRHR2 trafficking in mouse embryonic fibroblasts (MEFs) from either a ␤-arrestin 2 knockout or a ␤-arrestin 1/2 knockout, while TRHR1 trafficking was only abolished in MEFs lacking both ␤-arrestins. The differential ␤-arrestin-dependence of TRHR2 was directly measured in live cells using bioluminescence resonance energy transfer (BRET). Both BRET and confocal microscopy were also used to demonstrate that TRHR subtypes form hetero-oligomers. In addition, these hetero-oligomers have altered internalization kinetics compared with the homo-oligomer. The formation of TRHR1/2 heteromeric complexes increased the interaction between TRHR2 and ␤-arrestin 1. This may be due to conformational differences between TRHR1/2 hetero-oligomers versus TRHR2 homo-oligomers as a mutant TRHR1 (TRHR1 C335Stop) that does not interact with ␤-arrestins, could also enhance TRHR2/␤-arrestin 1 interaction. This study demonstrates that TRHR subtypes are differentially regulated by the ␤-arrestins and also provides the first evidence that the interactions of TRHRs with ␤-arrestin may be altered by hetero-oligomer formation. G-protein-coupled receptor (GPCR)1 function is underpinned by the formation of protein-protein interactions and complexes that are dynamically regulated by a variety of stimuli. These molecular interactions are involved in receptor recognition, activation, and desensitization and are targets for the majority of current therapeutic compounds utilized to treat a variety of disorders. More recently, the escalating body of evidence for GPCR oligomerization also adds another level of complexity in understanding how GPCRs are activated and signal and traffick in the cell. GPCR hetero-oligomerization may explain the diverse physiological responses obtained from a single ligand. Indeed, a number of GPCR subtypes such as the somatostatin, opioid, angiotensin, and ␤-adrenergic receptors have been shown to form hetero-oligomers that result in a receptor unit with either altered ligand specificity, signaling, or internalization rates (1-5). GPCR activation is also regulated by receptorprotein interactions involved in desensitization and internalization. For the majority of GPCRs, the mechanism of internalization is via the ␤-arrestin and dynamin-dependent pathway where agonist-activated phosphorylated receptors interact with the ␤-arres...

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Cloning and Characterization of a New Subtype of Thyrotropin-Releasing Hormone Receptors

Cited by 88 publications

References 0 publications

Expression of thyrotropin-releasing hormone receptor in immortalized beta-cell lines and rat pancreas

Expression of thyrotropin-releasing hormone receptor in immortalized beta-cell lines and rat pancreas

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

Homo- and Hetero-oligomerization of Thyrotropin-releasing Hormone (TRH) Receptor Subtypes

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