Cellular colocalization and coregulation between hypothalamic pro-TRH and prohormone convertases in hypothyroidism

Espinosa, Veronica Paez; Ferrini, Mónica G.; Shen, Xiaoxiong; Lutfy, Kabirullah; Nillni, Eduardo A.; Friedman, Theodore C.

doi:10.1152/ajpendo.00288.2006

Cited by 24 publications

(8 citation statements)

References 54 publications

(50 reference statements)

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“…It is synthesized as a propeptide precursor of 242 amino acids and posttranslationally processed by endopeptidases (proconvertases 1 and 2) which release 5 mature TRH molecules per propeptide molecule [20]. Endopeptidases therefore represent a first regulatory step of the amount of mature TRH molecules with functional impact [21].…”

Section: Hormonal Mechanisms Controlling Thyroid-stimulating Hormone mentioning

confidence: 99%

Central Hypothyroidism in Children

García

Fernández

Moreno³

2014

Paediatric Thyroidology

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Central congenital hypothyroidism (CCH) is an underdiagnosed disorder poorly described in childhood and adolescence. Congenital defects in thyroid-stimulating hormone (TSH) synthesis, secretion or bioactivity may lead to a state of 'regulatory' hypothyroidism expressed through aberrantly low or normal TSH levels and low thyroxine (T4), a hormonal pattern undetectable by TSH-based neonatal screening programs for congenital hypothyroidism (CH) implemented in most countries worldwide. CCH is more prevalent than previously thought, reaching 1 in 16,000 neonates in countries consistently identifying CCH through T4-based CH screening strategies. Neonatal detection and early treatment of CCH would prevent the risk of developing mental retardation secondary to late diagnosis of infantile hypothyroidism. CCH is frequently associated with other pituitary defects causing life-threatening situations (like e.g. adrenocorticotropic hormone deficiency) which could benefit from the early detection of CCH, avoiding considerable morbidity and mortality. CCH is not easy to identify clinically, and therefore few children are investigated for the disorder. The current knowledge on the genetic bases of CCH is also scarce. At the hypothalamic level no gene defects causing CCH have yet been identified in humans, but pituitary (thyrotrope)-selective genes encoding the TSH-releasing hormone (TRH) receptor (TRHR), the TSH β-subunit (TSHB) and, recently, the immunoglobulin superfamily factor 1 (IGSF1) are genes involved in isolated central hypothyroidism. Moreover, central hypothyroidism is a complex condition where many regulatory signals are implicated and converge to finely modulate the activity of the hypothalamic-pituitary-thyroid axis. This review focuses on novel pathogenic mechanisms and their implications to understand human CCH and improve the identification and the therapeutic handling of this elusive disease in the pediatric age.

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Section: Hormonal Mechanisms Controlling Thyroid-stimulating Hormone mentioning

confidence: 99%

Central Hypothyroidism in Children

García

Fernández

Moreno³

2014

Paediatric Thyroidology

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“…Changes in the thyroid status also have an effect on the processing of proTRH by altering the PCs (88,89). Interestingly, these changes in proTRH processing were observed only in hypophysiotropic proTRH neurons.…”

Section: Protrhmentioning

confidence: 99%

Regulation of Prohormone Convertases in Hypothalamic Neurons: Implications for ProThyrotropin-Releasing Hormone and Proopiomelanocortin

Nillni

2007

Endocrinology

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Recent evidence demonstrated that posttranslational processing of neuropeptides is critical in the pathogenesis of obesity. Leptin or other physiological changes affects the biosynthesis and processing of many peptides hormones as well as the regulation of the family of prohormone convertases responsible for the maturation of these hormones. Regulation of energy balance by leptin involves regulation of several proneuropeptides such as proTRH and proopiomelanocortin. These proneuropeptide precursors require for their maturation proteolytic cleavage by the prohormone convertases 1 and 2 (PC1/3 and PC2). Because biosynthesis of mature peptides in response to leptin requires prohormone processing, it is hypothesized that leptin might regulate hypothalamic PC1/3 and PC2 expression, ultimately leading to coordinated processing of prohormones into mature peptides. Leptin has been shown to increase PC1/3 and PC2 promoter activities, and starvation of rats, leading to low serum leptin levels, resulted in a decrease in PC1/3 and PC2 gene and protein expression in the paraventricular and arcuate nucleus of the hypothalamus. Changes in nutritional status also changes proopiomelanocortin processing in the nucleus of the solitary tract, but this is not reversed by leptin. The PCs are also physiologically regulated by states of hyperthyroidism, hyperglycemia, inflammation, and suckling, and a recently discovered nescient helix-loop-helix-2 transcription factor is the first one to show an ability to regulate the transcription of PC1/3 and PC2. Therefore, the coupled regulation of proneuropeptide/processing enzymes may be a common process, by which cells generate more effective processing of prohormones into mature peptides. (Endocrinology 148: 4191-4200, 2007)

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“…The PCs have been shown to be regulated by several factors, including by dopamine receptor agonists/antagonists [2, 3, 8], CRH [3], glucose [41], suckling [33], glucocorticoids [8] and thyroid hormone [8]. Our laboratories has extensively studied the regulation of the PCs by cytokines [25], hyperglycemia [31, 32], thyroid status [10, 23, 26, 45, 46] and fasting/feeding [39]. Opioid withdrawal was associated with increased PC2 protein levels in the midbrain periaqueductal gray matter [34] and we recently demonstrated that short-term morphine exposure down-regulated hypothalamic PC1/3 and PC2 protein levels, while long-term morphine exposure up-regulated expression of these proteins [11].…”

Section: Introductionmentioning

confidence: 99%

Morphine treatment selectively regulates expression of rat pituitary POMC and the prohormone convertases PC1/3 and PC2

et al. 2013

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The prohormone convertases, PC1/3 and PC2 are thought to be responsible for the activation of many prohormones through processing including the endogenous opioid peptides. We propose that maintenance of hormonal homeostasis can be achieved, in part, via alterations in levels of these enzymes that control the ratio of active hormone to prohormone. In order to test the hypothesis that exogenous opioids regulate the endogenous opioid system and the enzymes responsible for their biosynthesis, we studied the effect of short-term morphine or naltrexone treatment on pituitary PC1/3 and PC2 as well as on the level of pro-opiomelanocortin (POMC), the precursor gene for the biosynthesis of the endogenous opioid peptide, beta-endorphin. Using ribonuclease protection assays, we observed that morphine down-regulated and naltrexone up-regulated rat pituitary PC1/3 and PC2 mRNA. Immunofluorescence and Western blot analysis confirmed that the protein levels changed in parallel with the changes in mRNA levels and were accompanied by changes in the levels of phosphorylated cyclic-AMP response element binding protein. We propose that the alterations of the prohormone processing system may be a compensatory mechanism in response to an exogenous opioid ligand whereby the organism tries to restore its homeostatic hormonal milieu following exposure to the opioid, possibly by regulating the levels of multiple endogenous opioid peptides and other neuropeptides in concert.

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Cellular colocalization and coregulation between hypothalamic pro-TRH and prohormone convertases in hypothyroidism

Abstract: Espinosa VP, Ferrini M, Shen X, Lutfy K, Nillni EA, Friedman TC. Cellular colocalization and coregulation between hypothalamic pro-TRH and prohormone convertases in hypothyroidism.

Cited by 24 publications

References 54 publications

Central Hypothyroidism in Children

Central Hypothyroidism in Children

Regulation of Prohormone Convertases in Hypothalamic Neurons: Implications for ProThyrotropin-Releasing Hormone and Proopiomelanocortin

Morphine treatment selectively regulates expression of rat pituitary POMC and the prohormone convertases PC1/3 and PC2

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