Thyrotropin-releasing hormone receptors -- similarities and differences

Sun, Yongxing; Lu, Xiaoyong; Mc, Gershengorn

doi:10.1677/jme.0.0300087

Cited by 156 publications

(136 citation statements)

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“…It is also recognized that TRHR2 is not present in humans (Gloriam et al, 2007;Sun et al, 2003). We also confirmed independently using the blastp algorithm [http://blast.ncbi.nlm.nih.gov/] that no ortholog exists in human for mouse or rat TRHR2.…”

Section: A C C E P T E D Accepted Manuscriptsupporting

confidence: 73%

“…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%

“…and amino acid level (Sun et al, 2003). It is also recognized that TRHR2 is not present in humans (Gloriam et al, 2007;Sun et al, 2003).…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

“…Therefore, these ligands cannot be used to discriminate pharmacologically between the two receptors (Kelly et al, 2002;O'Dowd et al, 2000;Sun et al, 2003). Our previous studies in rat show that JAK4D displaces [ 3 H][3-Me-His 2 ]TRH binding to native cortical and hippocampal tissue, yet it does not displace this radiolabel in rat pituitary tissue (Hogan et al, 2008;Scalabrino et al, 2007), in which TRHR1 is highly expressed (Sun et al, 2003). If TRHR1 were the only TRH receptor in human tissue, it could be surmised from these rat studies that JAK4D would not bind to TRH receptors in either human pituitary or brain.…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

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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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Section: A C C E P T E D Accepted Manuscriptsupporting

confidence: 73%

Section: Accepted Manuscriptmentioning

confidence: 99%

“…and amino acid level (Sun et al, 2003). It is also recognized that TRHR2 is not present in humans (Gloriam et al, 2007;Sun et al, 2003).…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

See 2 more Smart Citations

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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show abstract

“…Inactivation of TSHR declines the thyroglobulin gene expression by the arbitration of c-AMP and concentration of thyroid hormones. Moreover, it belongs to G Protein Coupled Receptor (GPCR) family (Sun et al 2003) which found on surface of the cell membrane whereas thyroid receptor is a nuclear receptor. This means that targeting TSHR is less cumbersome as compared to thyroid receptor for drug molecules (Schapira et al 2003) and makes the bioavailability of drug for TSHR as compare to thyroid receptor.…”

Section: Simulation Analysis Of the Constructed Modelmentioning

confidence: 99%

Modeling and simulation analysis of propyl-thiouracil (PTU), an anti-thyroid drug on thyroid peroxidase (TPO), thyroid stimulating hormone receptor (TSHR), and sodium iodide (NIS) symporter based on systems biology approach

Gupta

Misra

2013

Netw Model Anal Health Inform Bioinforma

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The aim of metabolic modeling was to understand the cause effect interaction and reliance linked with the complex interactions of biological networks and molecular systems. Drugs that therapeutically modulate the biological processes of disease are often developed with limited knowledge of the underlying complexity of their specific targets. The robustness for systemic modulating behavior of thyroid hormone secretion during the course of different time unit simulation is explained in this study. In this work, a computational model has been developed which mimics the in vivo simulation. The model was constructed with the help of cell designer 4.1 used for analyzing the effect of perturbed amount of drugs at 0.1, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0 amounts as a unit, targeting Thyroid Peroxidase (TPO), Thyroid Stimulating Hormone Receptor (TSHR), and Sodium Iodide Symporter (NIS). The rate kinetic equations were defined with each reaction to simulate the molecular species dynamic behavior. The modulating behavior of thyroid hormone secretion was analyzed by the process of activation and inactivation states of TPO, TSHR, and NIS at various amounts of drugs.Obtained results explain suitably the entire observable fact of the drug effects and are capable to proceed in response to the perturbations of the natural cell. TSHR was found as the most potent molecular therapeutic target in this study.

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Hormones, 2. Peptides and Proteins: Hypothalamic–Pituitary and Calcitropic Hormones

Sandow

2013

Ullmann's Encyclopedia of Industrial Chemistry

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The article contains sections titled: 1. Introduction 2. Hypothalamic and Pituitary Hormones 2.1. The Hypothalamic–Pituitary System 2.2. Pituitary Hormone Preparations 2.2.1. Thyrotropin‐Releasing Hormone (TRH) 2.2.2. Thyrotropin (TSH) 2.2.3. Luteinizing Hormone Releasing Hormone (LHRH, GnRH) 2.2.4. Luteinizing Hormone (LH), Follitropin (FSH), Human Chorionic Gonadotropin (HCG) 2.3. Growth Hormone and Prolactin Regulation 2.3.1. Growth‐Hormone‐Releasing Hormone 2.3.2. Somatostatin 2.3.3. Growth Hormone 2.3.4. Prolactin and Human Placental Lactogen (HPL) 2.4. The Melanocortin System 2.4.1. Corticotropin‐Releasing Hormone (CRH) 2.4.2. Corticotropin (ACTH) 2.4.3. Melanocyte‐Stimulating Hormone (MSH) 2.4.4. Melanocortins 2.4.5. Proopiomelanocortin (POMC) Processing 2.5. New Hypothalamic–Pituitary Peptides 2.6. Neurohypophyseal Peptides 2.6.1. Vasopressin 2.6.2. Oxytocin 3. Calcium‐Regulating Hormones 3.1. Calcitonin 3.2. Parathormone

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Thyrotropin-releasing hormone receptors -- similarities and differences

Abstract: Thyrotropin-releasing hormone (TRH) initiates its effects by interacting with cell-surface membrane

Cited by 156 publications

References 58 publications

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

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

Modeling and simulation analysis of propyl-thiouracil (PTU), an anti-thyroid drug on thyroid peroxidase (TPO), thyroid stimulating hormone receptor (TSHR), and sodium iodide (NIS) symporter based on systems biology approach

Hormones, 2. Peptides and Proteins: Hypothalamic–Pituitary and Calcitropic Hormones

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