Thyrotropin Releasing Hormone (TRH), the TRH-Receptor and the TRH-Degrading Ectoenzyme; Three Elements of a Peptidergic Signalling System

Bauer, Karl; Schomburg, Lutz; Heuer, Heike; Schäfer, Martin

doi:10.1007/978-3-540-49421-8_2

“…These findings strongly suggest a physiological role of this peptidase for the regulation of the biological activity of neuronally released TRH. 2,3,19) On the other hand, immunoblot analysis showed the cytosolic distribution of PAP-I, being consistent with the subcellular localization of PAP-I activity in rat liver. 13) Immunohistochemical localization study of PAP-I demonstrated intracellular distribution in the pituitary, the target tissue of TRH.…”

Section: Discussionsupporting

confidence: 81%

“…2,4,5) Higher specific activity levels of PAP-II are found in the cerebral cortex, olfactory bulb, hippocampus and cerebellum, but lower levels are present in the spinal cord. 6,20,21) Heuer et al 3) have demonstrated that basal PAP-II activity in the pituitary is very low, but the activity and the mRNA levels of adenohypophyseal PAP-II are dramatically increased by thyroid hormones, whereas PAP-II activities in other brain regions are not, showing that adenohypophyseal PAP-II activity is stringently regulated by thyroid hormones.…”

Section: Discussionmentioning

confidence: 99%

“…All the TRH mediated metabolites other than unknown metabolite(s) were consistent with those reported previously. 2,11) Immunoblot Analysis Male F344/DuCrj rat liver, kidney and brain cytosolic or microsomal fractions and a polyclonal antibody raised against rat PAP-I in rabbits were prepared as previously described. 13) SDS-PAGE analysis of denatured samples (7-28 mg protein) was performed on 12.5% gels according to the method of Laemmli.…”

Section: )mentioning

confidence: 99%

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Marginal Involvement of Pyroglutamyl Aminopeptidase I in Metabolism of Thyrotropin-Releasing Hormone in Rat Brain

Abe

¹

,

Fukuda

²

,

Tokui

³

2004

Biological & Pharmaceutical Bulletin

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Thyrotropin-releasing hormone (TRH) is a peptide hormone released from hypothalamic tissue and stimulates the release of thyroid-stimulating hormone (thyrotropin) from the mammalian anterior pituitary by binding to the TRH receptor on the cell surface of the pituitary.1,2) TRH is a tripeptide with the amino acid sequence L-pyroglutamyl-L-histidyl-L-prorineamide (L-pGlu-His-Pro-NH 2 ). The wide distribution of TRH throughout the central nervous system and the findings of various biochemical, pharmacological and behavioral studies strongly suggest that TRH likely acts as a neuromodulator/neurotransmitter in extrahypothalamic brain areas. 2,3)Current evidence strongly indicates that pyroglutamyl aminopeptidase II EC 3.4.19.6) is the principal enzyme responsible for terminating the actions of neuronally released TRH by removing the L-pGlu residue.4-6) PAP-II is a membrane-anchored zinc-metalloenzyme primarily located in the central nervous system and is known as a highly specific enzyme for TRH and very closely related compounds. 1,7)Pyroglutamyl aminopeptidase I (PAP-I, EC 3.4.19.3), a typical cytosolic cysteine peptidase, also can hydrolyze TRH as well as bioactive neuropeptides such as luliberin (LH-RH) and neurotensin due to its broad substrate specificity. [8][9][10] But the cytosolic peptidases are generally considered to have no role in the metabolism of these bioactive peptides, because neuropeptides are commonly hydrolyzed by ectoenzymes localized on the membrane of cells with the active site facing the extracellular space or by lysosomal peptidases after endocytosis.1,11) Nevertheless, the contribution of cytosolic PAP-I to the hydrolysis of TRH in vivo is controversial. Charli et al. 6) reported that pGlu diazomethyl ketone, a PAP-I inhibitor, did not enhance TRH levels in the brain in vivo or in vitro, but Faivre-Bauman et al. 12) observed increased levels of TRH when primary cultures of hypothalamic cells were treated with Z-Gly-ProCHN 2 , also known as a PAP-I inhibitor.Recently we expressed the functional forms of rat, mouse and human PAP-Is by Escherichia coli as a single protein and obtained an antibody raised against rat recombinant PAP-I. 13)Using these preparations, we showed that L-pGlu p-nitroanilide (L-pGlu-pNA) is a good non-peptide synthetic substrate for recombinant PAP-Is and is hydrolyzed solely by cytosolic PAP-I from the immunoprecipitation study using the antibody.13) We also demonstrated that the liver and kidney show relatively high PAP-I activities compared with other tissues tested.13) More recently we found that PAP-I is involved in the hydrolysis of some xenobiotic compounds having an LpGlu or L-pGlu-related structure, now under development in our company. 14,15) In this study, by using the recombinant PAP-Is and the antibody against rat PAP-I, we investigated the possible contribution of PAP-I to the degradation of TRH in rats based on biochemical experiments in brain subcellular fractions and immunohistochemical localization of PAP-I in the brain as well as the liver and kid...

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“…This hypothesis was substantiated by the overlapping distribution of TRH-DE and TRH-R1 (the only TRHϩ receptor known until recently) in many hypothalamic and visceral brainstem regions. However, the observed discrepancies (in particular in the cerebral cortex and cerebellum) led us to postulate the existence of more than one receptor for TRH (Bauer et al, 1999), and therefore, we were most interested in studying the expression pattern of TRH-R2 discovered in the meantime (Cao et al, 1998;Itadani et al, 1998). With improved techniques we also reexamined the mRNA expression pattern of TRH in order to gain further insights as to the origin of the receptor ligands.…”

Section: Discussionmentioning

confidence: 97%

“…Although the hormonally regulated TRH-DE of the pituitary appears to serve regulatory functions, the high activities of TRH-DE in brain suggests that in the CNS this enzyme may act as a terminator of TRH signals (for review, see Bauer et al, 1999). For such functions it is interesting to note that TRH-DE appears to hydrolyze selectively TRH and structurally closely related synthetic peptides but none of the naturally occurring neuropeptides tested so far.…”

mentioning

confidence: 96%

Expression of thyrotropin-releasing hormone receptor 2 (TRH-R2) in the central nervous system of rats

Heuer¹,

Schäfer

²

,

O’Donnell

³

et al. 2000

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The distribution of the recently discovered thyrotropin-releasing hormone (TRH) receptor subtype TRH-R2 was studied in rat brain, pituitary, and spinal cord by in situ hybridization histochemistry and compared with the distribution patterns of the other elements of TRH signaling, namely TRH, TRH-R1, and the TRH-degrading ectoenzyme (TRH-DE). In contrast to the very restricted mRNA expression of TRH-R1 in the central nervous system, TRH-R2 mRNA was widely distributed with highest transcript levels throughout the thalamus, in the cerebral and cerebellar cortex, medial habenulae, medial geniculate nucleus, pontine nuclei, and throughout the reticular formation. In accordance with the well-known endocrine function of TRH, TRH-R1 is found predominantly expressed in hypothalamic regions. Expression of TRH-R1 in various brainstem nuclei and spinal cord motoneurons seems to be associated with the described effects of TRH on the vegetative and autonomic system as well as on the somatomotor system. Furthermore, the fully complementary expression of both receptor subtypes, even in regions where transcripts for both receptors were found (e.g., medial septum, lateral hypothalamus superior colliculi, substantia nigra, etc.), indicates that in discrete neuroanatomical pathways the two receptors serve highly specific functions for the transmission of TRH signals. Together with TRH-DE, the putative terminator of TRH actions that shows in various, but not all, brain areas, an overlapping mRNA distribution pattern with both receptors, the distribution of TRH-R2 mRNA seems to provide the anatomical basis for the described effects of TRH on higher cognitive functions as well as its effect on arousal, locomotor activity, and pain perception.

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

Sandow

¹

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 (TRH), the TRH-Receptor and the TRH-Degrading Ectoenzyme; Three Elements of a Peptidergic Signalling System

Cited by 20 publications

References 134 publications

Marginal Involvement of Pyroglutamyl Aminopeptidase I in Metabolism of Thyrotropin-Releasing Hormone in Rat Brain

Marginal Involvement of Pyroglutamyl Aminopeptidase I in Metabolism of Thyrotropin-Releasing Hormone in Rat Brain

Expression of thyrotropin-releasing hormone receptor 2 (TRH-R2) in the central nervous system of rats

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

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