193 results on '"Hormone receptors -- Physiological aspects"'
Search Results
2. Structures of full-length glycoprotein hormone receptor signalling complexes
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Duan, Jia, Xu, Peiyu, Cheng, Xi, Mao, Chunyou, Croll, Tristan, He, Xinheng, Shi, Jingjing, Luan, Xiaodong, Yin, Wanchao, You, Erli, Liu, Qiufeng, Zhang, Shuyang, Jiang, Hualiang, Zhang, Yan, Jiang, Yi, and Xu, H. Eric
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Glycoproteins -- Physiological aspects ,Hormone receptors -- Physiological aspects ,Protein research ,Cellular signal transduction -- Research ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Luteinizing hormone and chorionic gonadotropin are glycoprotein hormones that are related to follicle-stimulating hormone and thyroid-stimulating hormone.sup.1,2. Luteinizing hormone and chorionic gonadotropin are essential to human reproduction and are important therapeutic drugs.sup.3-6. They activate the same G-protein-coupled receptor, luteinizing hormone-choriogonadotropin receptor (LHCGR), by binding to the large extracellular domain.sup.3. Here we report four cryo-electron microscopy structures of LHCGR: two structures of the wild-type receptor in the inactive and active states; and two structures of the constitutively active mutated receptor. The active structures are bound to chorionic gonadotropin and the stimulatory G protein (G.sub.s), and one of the structures also contains Org43553, an allosteric agonist.sup.7. The structures reveal a distinct 'push-and-pull' mechanism of receptor activation, in which the extracellular domain is pushed by the bound hormone and pulled by the extended hinge loop next to the transmembrane domain. A highly conserved 10-residue fragment (P10) from the hinge C-terminal loop at the interface between the extracellular domain and the transmembrane domain functions as a tethered agonist to induce conformational changes in the transmembrane domain and G-protein coupling. Org43553 binds to a pocket of the transmembrane domain and interacts directly with P10, which further stabilizes the active conformation. Together, these structures provide a common model for understanding the signalling of glycoprotein hormone receptors and a basis for drug discovery for endocrine diseases. Cryo-electron microscopy structures of the luteinizing hormone-choriogonadotropin receptor (LHCGR), in complex with G.sub.s and in various states of activation, reveal a distinct mechanism of receptor activation, with implications for drug discovery., Author(s): Jia Duan [sup.1] [sup.2] , Peiyu Xu [sup.1] [sup.2] , Xi Cheng [sup.1] , Chunyou Mao [sup.3] [sup.4] [sup.5] [sup.6] [sup.12] , Tristan Croll [sup.7] , Xinheng He [sup.1] [...]
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- 2021
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3. Research from Faculdade de Medicina do ABC Yields New Data on Antidiuretic Hormones (Blockade of vasopressin receptors reduces the threshold pressure of micturition reflex in female rats)
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Medical research ,Medicine, Experimental ,Vasopressin -- Physiological aspects -- Health aspects ,Hormone receptors -- Physiological aspects ,Urination -- Research ,Health - Abstract
2022 OCT 22 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Investigators publish new report on antidiuretic hormones. According to news reporting out [...]
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- 2022
4. Studies in the Area of Steroid Receptors Reported from Max-Planck-Institute for Psychiatry (Cell-type-specific Impact of Glucocorticoid Receptor Activation On the Developing Brain: a Cerebral Organoid Study)
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Brain research ,Cerebral cortex -- Models -- Physiological aspects ,Corticosteroids -- Physiological aspects ,Fetus -- Growth ,Hormone receptors -- Physiological aspects ,Cell culture -- Usage ,Neurogenesis -- Models -- Research ,Health - Abstract
2022 JUL 2 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Investigators discuss new findings in Proteins - Steroid Receptors. According to news [...]
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- 2022
5. Constitutively active follicle-stimulating hormone receptor enables androgen-independent spermatogenesis
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Oduwole, Olayiwola O., Peltoketo, Hellevi, Poliandria, Ariel, Vengadabady, Laura, Chrusciel, Marcin, Doroszko, Milena, Samanta, Luna, Owen, Laura, Keevil, Brian, Rahman, Nafis A., and Huhtaniemi, Ilpo T.
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Spermatogenesis -- Research ,Follicle-stimulating hormone -- Physiological aspects ,Testosterone -- Physiological aspects ,Medical research ,Hormone receptors -- Physiological aspects ,Male infertility -- Research ,Health care industry - Abstract
Spermatogenesis is regulated by the 2 pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This process is considered impossible without the absolute requirement of LH-stimulated testicular testosterone (T) production. The role of FSH remains unclear because men and mice with inactivating FSH receptor (FSHR) mutations are fertile. We revisited the role of FSH in spermatogenesis using transgenic mice expressing a constitutively strongly active FSHR mutant in a LH receptor-null (LHR-null) background. The mutant FSHR reversed the azoospermia and partially restored fertility of [Lhr.sup.-/-] mice. The finding was initially ascribed to the residual Leydig cell T production. However, when T action was completely blocked with the potent antiandrogen flutamide, spermatogenesis persisted. Hence, completely T-independent spermatogenesis is possible through strong FSHR activation, and the dogma of T being a sine qua non for spermatogenesis may need modification. The mechanism for the finding appeared to be that FSHR activation maintained the expression of Sertoli cell genes considered androgen dependent. The translational message of our findings is the possibility of developing a new strategy of high- dose FSH treatment for spermatogenic failure. Our findings also provide an explanation of molecular pathogenesis for Pasqualini syndrome (fertile eunuchs; LH/T deficiency with persistent spermatogenesis) and explain how the hormonal regulation of spermatogenesis has shifted from FSH to T dominance during evolution., Introduction It is textbook knowledge that spermatogenesis is impossible without luteinizing hormone-stimulated (LH-stimulated) testicular testosterone (T) production (1, 2). Human mutations and genetically modified mice provide further proof for this, [...]
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- 2018
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6. DWARF14 is a non-canonical hormone receptor for strigolactone
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Yao, Ruifeng, Ming, Zhenhua, Yan, Liming, Li, Suhua, Wang, Fei, Ma, Sui, Yu, Caiting, Yang, Mai, Chen, Li, Chen, Linhai, Li, Yuwen, Yan, Chun, Miao, Di, Sun, Zhongyuan, Yan, Jianbin, Sun, Yuna, Wang, Lei, Chu, Jinfang, Fan, Shilong, He, Wei, Deng, Haiteng, Nan, Fajun, Li, Jiayang, Rao, Zihe, Lou, Zhiyong, and Xie, Daoxin
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Plant hormones -- Physiological aspects ,Hormone receptors -- Physiological aspects ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Classical hormone receptors reversibly and non-covalently bind active hormone molecules, which are generated by biosynthetic enzymes, to trigger signal transduction. The / hydrolase DWARF14 (D14), which hydrolyses the plant branching hormone strigolactone and interacts with the F-box protein D3/MAX2, is probably involved in strigolactone detection. However, the active form of strigolactone has yet to be identified and it is unclear which protein directly binds the active form of strigolactone, and in which manner, to act as the genuine strigolactone receptor. Here we report the crystal structure of the strigolactone-induced AtD14D3ASK1 complex, reveal that Arabidopsis thaliana (At)D14 undergoes an open-to-closed state transition to trigger strigolactone signalling, and demonstrate that strigolactone is hydrolysed into a covalently linked intermediate molecule (CLIM) to initiate a conformational change of AtD14 to facilitate interaction with D3. Notably, analyses of a highly branched Arabidopsis mutant d14-5 show that the AtD14(G158E) mutant maintains enzyme activity to hydrolyse strigolactone, but fails to efficiently interact with D3/MAX2 and loses the ability to act as a receptor that triggers strigolactone signalling in planta. These findings uncover a mechanism underlying the allosteric activation of AtD14 by strigolactone hydrolysis into CLIM, and define AtD14 as a non-canonical hormone receptor with dual functions to generate and sense the active form of strigolactone., Author(s): Ruifeng Yao [1]; Zhenhua Ming [2]; Liming Yan [2]; Suhua Li [1]; Fei Wang [1]; Sui Ma [1]; Caiting Yu [1]; Mai Yang [1]; Li Chen [1]; Linhai Chen [...]
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- 2016
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7. Structural biology: Signal locked in
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Snowden, Kimberley C. and Janssen, Bart J.
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Plant hormones -- Physiological aspects ,Arabidopsis thaliana -- Physiological aspects ,Hormone receptors -- Physiological aspects ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Author(s): Kimberley C. Snowden (corresponding author) [1]; Bart J. Janssen (corresponding author) [1] A receptor and its associated hormone are often thought of as a lock and key, in which [...]
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- 2016
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8. Researchers from University of the Chinese Academy of Sciences Discuss Findings in Science [Triiodothyronine (T3) Promotes Brown Fat Hyperplasia Via Thyroid Hormone Receptor Alpha Mediated Adipocyte Progenitor Cell Proliferation]
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Cell proliferation -- Research ,Hormone receptors -- Physiological aspects ,Physiological research ,Triiodothyronine -- Physiological aspects ,Hyperplasia -- Physiological aspects ,Fat cells -- Physiological aspects ,Health ,Science and technology - Abstract
2022 JUL 15 (NewsRx) -- By a News Reporter-Staff News Editor at Science Letter -- Current study results on Science have been published. According to news reporting out of Shanghai, [...]
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- 2022
9. New Insect Physiology Study Findings Have Been Reported by Researchers at Academy of Sciences of the Czech Republic (A Decade With the Juvenile Hormone Receptor)
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Ecdysteroids -- Physiological aspects ,Hormone receptors -- Physiological aspects ,Zoological research ,Insects -- Physiological aspects ,Animal development -- Research ,Biological sciences ,Health - Abstract
2022 MAR 8 (NewsRx) -- By a News Reporter-Staff News Editor at Life Science Weekly -- Data detailed on Life Science Research - Insect Physiology have been presented. According to [...]
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- 2022
10. BACE2 plays a role in the insulin receptor trafficking in pancreatic [beta]-cells
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Casas, Silvia, Casini, Paola, Piquer, Sandra, Altirriba, Jordi, Soty, Maud, Cadavez, Lisa, Gomis, Ramon, and Novials, Anna
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Enzymes -- Physiological aspects ,Enzymes -- Research ,Insulin -- Physiological aspects ,Insulin -- Research ,Hormone receptors -- Physiological aspects ,Hormone receptors -- Research ,Pancreatic beta cells -- Physiological aspects ,Pancreatic beta cells -- Research ,Biological sciences - Abstract
BACE1 ([beta]-site amyloidogenic cleavage of precursor protein-cleaving enzyme 1) is a [beta]-secretase protein that plays a central role in the production of the [beta]-amyloid peptide in the brain and is thought to be involved in the Alzheimer's pathogenesis. In type 2 diabetes, amyloid deposition within the pancreatic islets is a pathophysiological hallmark, making crucial the study in the pancreas of BACE1 and its homologous BACE2 to understand the pathological mechanisms of this disease. The objectives of the present study were to characterize the localization of BACE proteins in human pancreas and determine their function. High levels of BACE enzymatic activity were detected in human pancreas. In normal human pancreas, BACE1 was observed in endocrine as well as in exocrine pancreas, whereas BACE2 expression was restricted to [beta]-cells. Intracellular analysis using immunofluorescence showed colocalization of BACE1 with insulin and BACE2 with clathrin-coated vesicles of the plasma membrane in MIN6 cells. When BACE1 and -2 were pharmacologically inhibited, BACE1 localization was not altered, whereas BACE2 content in clathrin-coated vesicles was increased. Insulin internalization rate was reduced, insulin receptor [beta]-subunit (IR[beta]) expression was decreased at the plasma membrane and increased in the Golgi apparatus, and a significant reduction in insulin gene expression was detected. Similar results were obtained after specific BACE2 silencing in MIN6 cells. All these data point to a role for BACE2 in the IR[beta] trafficking and insulin signaling. In conclusion, BACE2 is hereby presented as an important enzyme in [beta]-cell function. [beta]-site amyloidogenic cleavage of precursor protein-cleaving enzyme 1; [beta]-secretase; pancreas; insulin receptor [beta]-subunit trafficking doi: 10.1152/ajpendo.00420.2010.
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- 2010
11. Cardiac oxytocin receptor blockade stimulates adverse cardiac remodeling in ovariectomized spontaneously hypertensive rats
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Jankowski, Marek, Wang, Donghao, Danalache, Bogdan, Gangal, Marius, and Gutkowska, Jolanta
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Cardiovascular diseases -- Risk factors ,Cardiovascular diseases -- Care and treatment ,Cardiovascular diseases -- Research ,Hormone receptors -- Physiological aspects ,Hormone receptors -- Research ,Isoflavones -- Health aspects ,Isoflavones -- Research ,Ovariectomy -- Complications and side effects ,Ovariectomy -- Research ,Biological sciences - Abstract
An increasing amount of evidence demonstrates the beneficial role of oxytocin (OT) in the cardiovascular system. Similar actions are attributed to genistein, an isoflavonic phytoestrogen. The treatment with genistein activates the OT system in the aorta of ovariectomized (OVX) Sprague-Dawley (SD) rats. The objective of this study was to determine the effects of low doses of genistein on the OT-induced effects in rat hypertension. The hypothesis tested was that treatment of OVX spontaneously hypertensive rats (SHRs) with genistein improves heart structure and heart work through a mechanism involving the specific OT receptor (OTR). OVX SHRs or SD rats were treated with genistein (in [micro]g/g body wt sc, 10 days) in the presence or absence of an OT antagonist (OTA) [d[(C[H.sub.2]).sub.5], Tyr[(Me).sup.2], [Orn.sup.8]]-vasotocin or a nonspecific estrogen receptor antagonist (ICI-182780). Vehicle-treated OVX rats served as controls. RT-PCR and Western blot analysis demonstrated that left ventricular (LV) OTR, downregulated by ovariectomy, increased in response to genistein. In SHRs or SD rats, this effect was blocked by OTA or ICI-182780 administration. The OTR was mainly localized in microvessels expressing the CD31 marker and colocalized with endothelial nitric oxide synthase. In SHRs, the genistein-stimulated OTR increases were associated with improved fractional shortening, decreased blood pressure (12 mmHg), decreased heart weight-to-body weight ratio, decreased fibrosis, and lowered brain natriuretic peptide in the LV. The prominent finding of the study is the detrimental effect of OTA treatment on the LV of SHRs. OTA treatment of OVX SHRs resulted in a dramatic worsening of ejection fractions and an augmented fibrosis. In conclusion, these results demonstrate that cardiac OTRs are involved in the regulation of cardiac function of OVX SHRs. The decreases of OTRs may contribute to cardiac pathology following menopause. oxytocin receptor; ovariectomy; hypertrophy; genistein doi: 10.1152/ajpheart.00487.2009.
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- 2010
12. Functional divergence of glycoprotein hormone receptors
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Freamat, Mihael and Sower, Stacia A.
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Glycoproteins -- Physiological aspects ,Hormone receptors -- Natural history ,Hormone receptors -- Physiological aspects ,Lampreys -- Physiological aspects ,Lampreys -- Natural history ,Divergent evolution -- Research ,Zoology and wildlife conservation - Abstract
Two lamprey glycroprotein hormone receptors (1GpH-R I and II) highly similar with gnathostome GpH-Rs were cloned from sea lamprey testes and thyroid, respectively. Vertebrate glycoprotein protein receptors have a large extracellular domain (ED) containing a leu rich domain (LRD) linked to a rhodopsin-like transmembrane domain (TMD) through a highly divergent linker region (signal specificity domain, SSD or 'hinge' region) and a third major segment, the intracellular domain. To determine the potential roles of the different domains in the activation of the receptor following ligand-receptor binding, functional assays were performed on 1GpH-R I/rat luteinizing hormone (LH)-R domain swapped chimeric receptors. These results show that the functional roles of the lamprey glycoprotein-receptor I (1GpH-R I) domains are conserved compared with its Gnathostome homologs. The ability of different glycoprotein hormones to activate chimeric lamprey/rat receptors suggests that the selectivity of the GpH-Rs in respect to their ligands is not controlled exclusively by a single domain but is the result of specific interactions between domains. We hypothesize that these interactions were refined during millions of years of co-evolution of the receptors with their cognate ligands under particular intramolecular, intermolecular and physiological constraints. doi: 10.1093/icb/icq044
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- 2010
13. Isolation, expression analysis, and functional characterization of the first antidiuretic hormone receptor in insects
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Paluzzi, Jean-Paul, Park, Yoonseong, Nachman, Ronald J., and Orchard, Ian
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Hormone receptors -- Physiological aspects ,Hormone receptors -- Genetic aspects ,Hormone receptors -- Research ,Vasopressin -- Physiological aspects ,Vasopressin -- Genetic aspects ,Vasopressin -- Research ,Science and technology - Abstract
Diuresis following blood-gorging in Rhodnius prolixus is the major process leading to the transmission of Chagas' disease. We have cloned the cDNA of the first receptor known to be involved in an antidiuretic strategy in insects, a strategy that prevents diuresis. This receptor belongs to the insect CAPA receptor family known in other insects to be activated by peptides encoded within the capability gene. We characterize the expression profile in fifth-instars and find expression is localized to the alimentary canal. Highest transcript levels are found in Malpighian tubules and the anterior midgut, which are known targets of the antidiuretic hormone, RhoprCAPA-[alpha]2. Two transcripts were identified, capa-r1 and capa-r2; however, the latter encodes an atypical G protein-coupled receptor lacking a region ranging between the first and second transmembrane domain. Our heterologous expression assay revealed the expressed capa-r1 receptor is activated by RhoprCAPA-[alpha]2 ([EC.sub.50] = 385nM) but not by RhoprCAPA-[alpha]1. Structural analogs of the inactive RhoprCAPA-[alpha]1 were capable of activating the expressed capa-r1 receptor, confirming the importance of the C-terminal consensus sequence common to CAPA-related peptides. In addition, this receptor has some sensitivity to the pyrokininrelated peptide, RhoprCAPA-[alpha]PK1, but with an efficacy [approximately equal to] 40-fold less than RhoprCAPA-[alpha]2. Other peptides belonging to the PRXa-mide superfamily were inactive on the capa-r1 receptor. Taken together, the neuroendocrinological relevance of this receptor in facilitating the antidiuretic strategy in R. prolixus may make this receptor a useful target for development of agonists or antagonists that could help influence the transmission of Chagas' disease that occurs during diuresis in this medically important insect-disease vector. CAPA | Chagas' | G protein-coupled receptor | neurohormone | neuropeptide doi/ 10.1073/pnas.1003666107
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- 2010
14. Sensitivity of NOS-dependent vascular relaxation pathway to mineralocorticoid receptor blockade in caveolin-1-deficient mice
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Pojoga, Luminita H., Adamova, Zuzana, Kumar, Abhinav, Stennett, Amanda K., Romero, Jose R., Adler, Gail K., Williams, Gordon H., and Khalil, Raouf A.
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Caveolins -- Physiological aspects ,Caveolins -- Research ,Enzymes -- Physiological aspects ,Enzymes -- Research ,Hormone receptors -- Physiological aspects ,Hormone receptors -- Research ,Biological sciences - Abstract
Endothelial caveolin-I (cav-1) is an anchoring protein in plasma membrane caveolae where it binds endothelial nitric oxide synthase (eNOS) and limits its activation, particularly in animals fed a high salt (HS) diet. Cav-1 also interacts with steroid receptors such as the mineralocorticoid receptor (MR). To test the hypothesis that vascular reactivity is influenced by an interplay between MR and cav- 1 during HS diet, we examined the effects of MR blockade on NOS-mediated vascular relaxation in normal and cav-l-deficient mice. Wild-type (WT) and car-1 knockout mice ([cav-1.sup.-/-]) were fed for 14 days a HS (4% NaCl) diet with and without the MR antagonist eplerenone (Epl; 100 mg x [kg.sup.-1] x [day.sup.-1]). After systolic blood pressure (BP) was measured, the thoracic aorta was isolated for measurement of vascular reactivity, and the aorta and heart were used for measurement of eNOS and MR expression. BP was not different between WT + Epl and WT, but was higher in [cav-1.sup.-/-] + Epl than in [cav-1.sup.-/-] mice. Phenylephrine (Pbe)-induced vascular contraction was less in [cav-1.sup.-/-] than WT, and significantly enhanced in [cav-1.sup.-/-] + Epl than in [cav-1.sup.-/-] , but not in WT + Epl compared with WT. Endothelium removal and NOS blockade by [N.sup.[omega]]-nitro-L-arginine methyl ester (L-NAME) enhanced Phe contraction in [car-1.sup.-/-], but not [cav-1.sup.-/-] + Epl. ACh-induced aortic relaxation was reduced in [cav-1.sup.-/-] + Ep1 versus [cav-1.sup.-/-], but not in WT + Epl compared with WT. Endothelium removal, L-NAME, and the guanylate cyclase inhibitor ODQ abolished the large ACh-induced relaxation in [cav-1.sup.-/-] and the remaining relaxation in the [cav-1.sup.-/-] + Epl but had similar inhibitory effect in WT and WT + Epl. Real-time RT-PCR indicated decreased eNOS mRNA expression in the aorta and heart, and Western blots revealed decreased total eNOS in the heart of [cav-1.sup.-/-] + Epl compared with [cav-1.sup.-/-]. Vascular and cardiac MR expression was less in [cav-1.sup.-/-] than WT, but not in [cav-1.sup.-/-] + Epl compared with [cav-1.sup.-/-]. Plasma aldosterone (Aldo) was not different between WT and [cav-1.sup.-/-] mice nontreated or treated with Epl. Thus in cav-1 deficiency states and HS diet MR blockade is associated with increased BP, enhanced vasoconstriction, and decreased NOS-mediated vascular relaxation and eNOS expression. The data suggest that, in the absence of cav-1, MR activation plays a beneficial role in regulating eNOS expression/activity and, consequently, the vascular function during HS diet. caveolae; aldosterone; eplerenone; endothelium; endothelial nitric oxide synthase doi: 10.1152/ajpheart.00661.2009.
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- 2010
15. Brain vasopressin [V.sub.1] receptors contribute to enhanced cardiovascular responses to acute stress in chronically stressed rats and rats with myocardial infarcton
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Cudnoch-Jedrzejewska, Agnieszka, Szczepanska-Sadowska, Ewa, Dobruch, Jakub, Gomolka, Ryszard, and Puchalska, Liana
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Hormone receptors -- Physiological aspects ,Hormone receptors -- Genetic aspects ,Hormone receptors -- Research ,Stress (Psychology) -- Complications and side effects ,Vasopressin -- Physiological aspects ,Vasopressin -- Genetic aspects ,Heart failure -- Genetic aspects ,Biological sciences - Abstract
The present study was designed to determine the role of central vasopressin 1 receptors ([V.sub.1]R) in the regulation of cardiovascular parameters in chronically stressed infarcted rats and sham-operated rats under resting conditions and during exposure to acute alarming stress. The experiments were performed on four groups of conscious sham-operated and four groups of infarcted rats subjected to intraventricular infusion of either vehicle or a [V.sub.1]R antagonist ([V.sub.1]RANT). Two groups of infarcted and two groups of sham-operated rats were subjected to mild chronic stressing. Mean arterial blood pressure (MABP) and heart rate (HR) were determined under resting conditions and alter exposure to acute stress (air jet). During vehicle infusion, MABP and HR increases in response to acute stress in the infarcted rats not subjected to chronic stress, and in the infarcted and sham-operated chronically stressed rats, were significantly greater than in the sham-operated rats not exposed to chronic stress. However, MABP and HR responses to acute stress in the chronically stressed infarcted rats and chronically stressed sham-operated rats did not differ. [V.sub.1]RANT abolished differences in cardiovascular responses to acute stress between the experimental groups. Resting cardiovascular parameters were not affected by any of the experimental treatments. It is concluded that chronic stressing enhances the pressor and tachycardic responses to acute stress in the sham-operated rats but does not further intensify these responses in infarcted rats. The results provide evidence that central [V.sub.1]Rs are involved in potentiation of cardiovascular responses to acute stress in chronically stressed rats, infarcted rats, and chronically stressed infarcted rats. vasopressin 1 receptor antagonist; heart failure; tachycardia; depression doi:10.1152/ajpregu.00543.2009
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- 2010
16. Early weaning stress impairs development of mucosal barrier function in the porcine intestine
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Smith, Feli, Clark, Jessica E., Overman, Beth L., Tozel, Christena C., Huang, Jennifer H., Rivier, Jean E.F., Blisklager, Anthony T., and Moeser, Adam J.
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Colorectal diseases -- Risk factors ,Colorectal diseases -- Research ,Gastrointestinal diseases -- Risk factors ,Gastrointestinal diseases -- Research ,Stress (Psychology) -- Research ,Hormone receptors -- Physiological aspects ,Hormone receptors -- Research ,Biological sciences - Abstract
Early life stress is a predisposing factor for the development of chronic intestinal disorders in adult life. Here, we show that stress associated with early weaning in pigs leads to impaired mucosal barrier function. Early weaning (15- to 21-day weaning age) resulted in sustained impairment in intestinal barrier function, as indicated by reductions in jejunal transepithelial electrical resistance and elevations in mucosal-to-serosal flux of paracellular probes [sup.3]H]mannitol and [[sup.14]C]inulin measured at 5 and 9 wk of age, compared with that shown in late-weaned pigs (23- to 28-day weaning age). Elevated baseline short-circuit current was observed in jejunum from early-weaned pigs and was shown to be mediated via enhanced [Cl.sup.-] secretion. Jejunal barrier dysfunction in early-weaned pigs coincided with increased lamina propria immune cell density particularly mucosal mast cells. The mast cell stabilizer drug sodium cromoglycolate ameliorated barrier dysfunction and hypersecretion in early-weaned pigs, demonstrating an important role of mast cells. Furthermore, activation of mast cells ex vivo with c48/80 and corticotrophin-releasing factor (CRF) in pig jejunum mounted in Ussing chambers induced barrier dysfunction and elevations in short-circuit current that were inhibited with mast cell protease inhibitors. Experiments in which selective CRF receptor antagonists were administered to early-weaned pigs revealed that CRF receptor 1 (CRFr1) activation mediates barrier dysfunction and hypersecretion, whereas CRFr2 activation may be responsible for novel protective properties in the porcine intestine in response to early life stress. weaning age; mast cells; corticotropin releasing factor doi:10.1152/ajpgi.00081.2009.
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- 2010
17. RAGE supports parathyroid hormone-induced gains in femoral trabecular bone
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Philip, Binu K., Childress, Paul J., Robling, Alexander G., Heller, Aaron, Nawroth, Peter P., Bierhaus, Angelika, and Bidwell, Joseph P.
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Parathyroid hormone -- Physiological aspects ,Parathyroid hormone -- Research ,Hormone receptors -- Physiological aspects ,Hormone receptors -- Research ,Bones -- Density ,Bones -- Research ,Biological sciences - Abstract
Parathyroid hormone (PTH) restores bone mass to the osteopenic skeleton, but significant questions remain as to the underlying mechanisms. The receptor for advanced glycation end products (RAGE) is a multiligand receptor of the immunoglobulin superfamily; however, recent studies indicate a role in bone physiology. We investigated the significance of RAGE to hormone-induced increases in bone by treating 10-wk-old female Rage-knockout (KO) and wild-type (WT) mice with human PTH-(1-34) at 30 [micro]g x [kg.sup.-1] x [day.sup.-1] or vehicle control, 7 days/wk, for 7 wk. PTH produced equivalent relative gains in bone mineral density (BMD) and bone mineral content (BMC) throughout the skeleton in both genotypes. PTH-mediated relative increases in cortical area of the midshaft femur were not compromised in the null mice. However, the hormone-induced gain in femoral cancellous bone was significantly attenuated in Rage-KO mice. The loss of RAGE impaired PTH-mediated increases in femoral cancellous bone volume, connectivity density, and trabecular number but did not impact increases in trabecular thickness or decreases in trabecular spacing. Disabling RAGE reduced femoral expression of bone formation genes, but their relative PTH-responsiveness was not impaired. Neutralizing RAGE did not attenuate vertebral cancellous bone response to hormone. Rage-null mice exhibited an attenuated accrual rate of bone mass, with the exception of the spine, and an enhanced accrual rate of fat mass. We conclude that RAGE is necessary for key aspects of the skeleton's response to anabolic PTH. Specifically, RAGE is required for hormone-mediated improvement of femoral trabecular architecture but not intrinsically necessary for increasing cortical thickness. receptor for advanced glycation end products; anabolic; high-mobility group box 1 protein; osteoblast; osteoporosis; osteoimmunology doi:10.1152/ajpendo.00564.2009.
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- 2010
18. Pmch expression during early development is critical for normal energy homeostasis
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Mul, Joram D., Yi, Chun-Xia, van den Berg, Sjoerd A.A., Ruiter, Marieke, Toonen, Pim W., van der Elst, Martine C.J., Voshol, Peter J., Ellenbroek, Bart A., Kalsbeck, Andries, la Fleur, Susanne E., and Cuppen, Edwin
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Hormone receptors -- Physiological aspects ,Hormone receptors -- Research ,Neuropeptides -- Physiological aspects ,Neuropeptides -- Research ,Obesity in children -- Care and treatment ,Obesity in children -- Research ,Homeostasis -- Physiological aspects ,Homeostasis -- Research ,Biological sciences - Abstract
Postnatal development and puberty are times of strong physical maturation and require large quantities of energy. The hypothalamic neuropeptide melanin-concentrating hormone (MCH) regulates nutrient intake and energy homeostasis, but the underlying mechanisms are not completely understood. Here we use a novel rat knockout model in which the MCH precursor Pmch has been inactivated to study the effects of loss of MCH on energy regulation in more detail. [Pmch.sup.-/-] rats are lean, hypophagic, osteoporotic, and although endocrine parameters were changed in [pmch.sup.-/-] rats, endocrine dynamics were normal, indicating an adaptation to new homeostatic levels rather than disturbed metabolic mechanisms. Detailed body weight growth and feeding behavior analysis revealed that Pmch expression is particularly important during early rat development and puberty, i.e., the first 8 postnatal weeks. Loss of Pinch resulted in a 20% lower set point for body weight that was determined solely during this period and remained unchanged during adulthood. Although the final body weight is diet dependent, the Pmch-deficiency effect was similar for all diets tested in this study. Loss of Pinch affected energy expenditure in both young and adult rats, although these effects seem secondary to the observed hypophagia. Our findings show an important role for Pmch in energy homeostasis determination during early development and indicate that the MCH receptor 1 system is a plausible target for childhood obesity treatment, currently a major health issue in first world countries. melanin-concentrating hormone; hypothalamus: childhood obesity; rat knockout model doi:10.1152/ajpendo.00154.2009.
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- 2010
19. CRFR1 is expressed on pancreatic [beta] cells, promotes Cell proliferation, and potentiates insulin secretion a glucose-dependent manner
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Huising, Mark O., van der Meulen, Talitha, Vaughan, Joan M., Matsumoto, Masahito, Donaldson, Cynthia J., Park, Hannah, Billestrup, Nils, and Vale, Wylie W.
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Cell proliferation -- Research ,Hormone receptors -- Physiological aspects ,Hormone receptors -- Research ,Pancreatic beta cells -- Physiological aspects ,Pancreatic beta cells -- Research ,Insulin -- Physiological aspects ,Insulin -- Research ,Science and technology - Abstract
Corticotropin-releasing factor (CRF), originally characterized as the principal neuroregulator of the hypothalamus-pituitary-adrenal axis, has broad central and peripheral distribution and actions. We demonstrate the presence of CRF receptor type 1(CRFR1) on primary [beta] cells and show that activation of pancreatic CRFR1 promotes insulin secretion, thus contributing to the restoration of normoglycemic equilibrium. Stimulation of pancreatic CRFR1 initiates a cAMP response that promotes insulin secretion in vitro and in vivo and leads to the phosphorylation of cAMP response element binding and the induction of the expression of several immediate-early genes. Thus, the insulinotropic actions of pancreatic CRFR1 oppose the activation of CRFR1 on anterior pituitary corticotropes, leading to the release of glucocorticoids that functionally antagonize the actions of insulin. Stimulation of the MIN6 insulinoma line and primary rat islets with CRF also activates the MAPK signaling cascade leading to rapid phosphorylation of Erkl/2 in response to CRFR1-selective ligands, which induce proliferation in primary rat neonatal [beta] cells. Importantly, CRFR1 stimulates insulin secretion only during conditions of intermediate to high ambient glucose, and the CRFRl-dependent phosphorylation of Erk1/2 is greater with elevated glucose concentrations. This response is reminiscent of the actions of the incretins, which potentiate insulin secretion only during elevated glucose conditions. The presence of CRFR1 on [beta] cells adds another layer of complexity to the intricate network of paracrine and autocrine factors and their cognate receptors whose coordinated efforts can dictate islet hormone output and regulate [beta] cell proliferation. diabetes | pancreas | corticotropin-releasing factor | hypothalamus-pituitary-adrenal axis | glucose homeostasis www.pnas.org/cgi/doi/10.1073/pnas.0913610107
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- 2010
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20. Retinoic acid activation of peroxisome proliferation-activated receptor [delta] represses obesity and insulin resistance
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Wolf, George
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Obesity -- Prevention ,Insulin resistance -- Prevention ,Tretinoin -- Health aspects ,Hormone receptors -- Physiological aspects ,Hormone receptors -- Health aspects ,Peroxisomes -- Physiological aspects ,Peroxisomes -- Health aspects ,Food/cooking/nutrition - Abstract
Retinoic acid (RA) was found to be a ligand for peroxisome proliferation-activated receptor [delta] (PPAR[delta]) as well as the classical RA receptor (RAR). Carrier proteins that move the RA from the cytosol into the nucleus are the fatty acid-binding protein 5 (FABP5), activating PPAR[delta], and the cellular retinoic acid-binding protein II (CRABPII), activating RAR. The ratio of FABPS/CRABPII concentrations determines which receptor is activated. By activating PPAR[delta], RA was found to induce expression of genes affecting lipid and glucose homeostasis, in particular, leading to expression of the insulin-signaling gene PDK1 and improvement of insulin action. Hence, RA stimulates lipolysis and reduces triglyceride content. In vivo, obesity has led to downregulation of adipose PPAR[delta] expression. RA implantation into obese mice has caused upregulation of levels of PPAR[delta] and consequent weight loss as well as increased expression of PPAR[delta] target genes, including the insulin-signaling gene PDK1. doi: 10.1111/j.1753-4887.2009.00261.x
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- 2010
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21. Hypocretin/orexin increases the expression of steroidogenic enzymes in human adrenocortical NCI H295R cells
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Wenzel, Jan, Grabinski, Nicole, Knopp, Cordula A., Dendorfer, Andreas, Ramanjaneya, Manjunath, Randeva, Harpal S., Ehrhart-Bornstein, Monika, Dominiak, Peter, and Johren, Olaf
- Subjects
Adrenocortical hormones -- Physiological aspects ,Adrenocortical hormones -- Genetic aspects ,Adrenocortical hormones -- Research ,Cytochrome P-450 -- Physiological aspects ,Cytochrome P-450 -- Genetic aspects ,Cytochrome P-450 -- Research ,Hormone receptors -- Physiological aspects ,Hormone receptors -- Genetic aspects ,Hormone receptors -- Research ,Polymerase chain reaction -- Usage ,Biological sciences - Abstract
Hypocretins/orexins act through two receptor subtypes: [OX.sub.1] and [OX.sub.2]. Outside the brain, orexin receptors are expressed in adrenal glands, where orexins stimulate the release of glucocorticoids. To further address the regulation of steroidogenesis, we analyzed the effect of orexins on the expression of steroidogenic enzymes in human adrenocortical National Cancer Institute (NCI) H295R cells by qPCR. In NCI H295R cells, [OX.sub.2] receptors were highly expressed, as they were in human adrenal glands. After treatment of NCI H295R cells with orexin A for 12-24 h, the cortisol synthesis rate was significantly increased, whereas 30 min of treatment showed no effect. While CYP11B1 and CYP11B2 mRNA levels were increased already at earlier time points, the expression of HSD3B2 and CYP21 mRNA was significantly up-regulated after treatment with orexin A for 12 h. Likewise, orexin B increased CYP21 and HSD3B2 mRNA levels showing, however, a lower potency compared with orexin A. The mRNA levels of CYP11A and CYP17 were unaffected by orexin A. [OX.sub.2] receptor mRNA levels were down-regulated after 12 and 24 h of orexin A treatment. Orexin A increased intracellular [Ca.sup.2+] but not cAMP concentrations in NCI H295R cells. Furthermore, inhibition of PKC and MAPK kinase/ ERK kinase (MEK1/2) prevented the increase of HSD3B2 expression by orexin A. Accordingly, orexin A treatment of NCI H295R cells markedly enhanced ERK1/2 phosphorylation that was prevented by PKC and, in part, PKA inhibition. In conclusion, orexins may influence adrenal steroidogenesis by differential regulation of the expression of steroidogenic enzymes involving [Ca.sup.2+], as well as PKC-ERK1/2 signaling. hypocretin-1 and -2; [OX.sub.1] and [OX.sub.2] receptor; real-time reverse transcriptase-polymerase chain reaction; cortisol doi: 10.1152/ajpregu.91034.2008.
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- 2009
22. Agonist-induced internalization and downregulation of gonadotropin-releasing hormone receptors
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Finch, Ann R., Caunt, Christopher J., Armstrong, Stephen P., and McArdle, Craig A.
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Gene expression -- Research ,Gonadotropin releasing hormone -- Physiological aspects ,Gonadotropin releasing hormone -- Genetic aspects ,Gonadotropin releasing hormone -- Research ,Hormone receptors -- Physiological aspects ,Hormone receptors -- Research ,Biological sciences - Abstract
Gonadotropin-releasing hormone (GnRH) acts via seven transmembrane receptors to stimulate gonadotropin secretion. Sustained stimulation desensitizes GnRH receptor (GnRHR)-mediated gonadotropin secretion, and this underlies agonist use in hormone-dependent cancers. Since type I mammalian GnRHR do not desensitize, agonist-induced internalization and downregulation may underlie desensitization of GnRH-stimulated gonadotropin secretion; however, research focus has recently shifted to anterograde trafficking, with the finding that human (h)GnRHR are mostly intracellular. Moreover, there is little direct evidence for agonist-induced trafficking of hGnRHR, and whether or not type 1 mammalian GnRHR show agonist-induced internalization is controversial. Here we use automated imaging to monitor expression and internalization of hemagglutinin (HA)-tagged hGnRHRs, mouse (m) GnRHR, Xenopus (X) GnRHRs, and chimeric receptors (hGnRHR with added XGnRHR COOH tails, h.XGnRHR) expressed by adenoviral transduction in HeLa cells. We find that agonists stimulate downregulation and/or internalization of mGnRHR and XGnRHR, that GnRH stimulates trafficking of hGnRHR and can stimulate internalization or downregulation of hGnRHR when steps are taken to increase cell surface expression (addition of the XGnRHR COOH tail or pretreatment with pharmacological chaperone). Agonist effects on internalization (of h.XGnRHR) and downregulation (of hGnRHR and h.XGnRHR) were not mimicked by a peptide antagonist and were prevented by a mutation that prevents GnRHR signaling, demonstrating dependence on receptor signaling as well as agonist occupancy. Thus agonist-induced internalization and downregulation of type I mammalian GnRHR occurs in HeLa cells, and we suggest that the high throughput imaging systems described here will facilitate study of the molecular mechanisms involved. seven transmembrane receptor; trafficking; G protein-coupled receptor
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- 2009
23. Impaired defense mechanism against inflammation, hyperalgesia, and airway hyperreactivity in somatostatin 4 receptor gene-deleted mice
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Helyes, Zsuzsanna, Pinter, Erika, Sandor, Katalin, Elekes, Krisztian, Banvolgyi, Agnes, Keszthelyi, Daniel, Szoke, Eva, Toth, Daniel M., Sandor, Zoltan, Kereskai, Laszlo, Pozsgai, Gabor, Allen, Jeremy P., Emson, Piers C., Markovics, Adrienn, and Szolcanvi, Janos
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Animal models in research -- Usage ,Hormone receptors -- Physiological aspects ,Hormone receptors -- Research ,Somatostatin -- Research ,Somatostatin -- Physiological aspects ,Inflammation -- Research ,Inflammation -- Drug therapy ,Science and technology - Abstract
We have shown that somatostatin released from activated capsaicin-sensitive nociceptive nerve endings during inflammatory processes elicits systemic anti-inflammatory and analgesic effects. With the help of somatostatin receptor subtype 4 gene--deleted mice ([sst.sub.4.sup.-/-]), we provide here several lines of evidence that this receptor has a protective role in a variety of inflammatory disease models; several symptoms are more severe in the [sst.sub.4] knockout animals than in their wild-type counterparts. Acute carrageenan-induced paw edema and mechanical hyperalgesia, inflammatory pain in the early phase of adjuvant-evoked chronic arthritis, and oxazolone-induced delayed-type hypersensitivity reaction in the skin are much greater in mice lacking the [sst.sub.4] receptor. Airway inflammation and consequent bronchial hyperreactivity elicited by intranasal lipopolysaccharide administration are also markedly enhanced in [sst.sub.4] knockouts, including increased perivascular/peribronchial edema, neutrophil/macrophage infiltration, mucus-producing goblet cell hyperplasia, myeloperoxidase activity, and 1L-1[beta], TNF-[alpha], and IFN-[gamma] expression in the inflamed lung. It is concluded that during these inflammatory conditions the released somatostatin has pronounced counterregulatory effects through [sst.sub.4] receptor activation. Thus, this receptor is a promising novel target for developing anti-inflammatory, analgesic, and anti-asthmatic drugs. allergic contact dermatitis | arthritis | capsaicin-sensitive afferents | endotoxin-induced pneumonitis | inflammatory cytokines
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- 2009
24. Nuclear hormone receptor activity of polybrominated diphenyl ethers and their hydroxylated and methoxylated metabolites in transactivation assays using Chinese hamster ovary cells
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Kojima, Hiroyuki, Takeuchi, Shinji, Uramaru, Naoto, Sugihara, Kazumi, Yoshida, Takahiko, and Kitamura, Shigeyuki
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Hormone receptors -- Physiological aspects ,Hormone receptors -- Research ,Metabolites -- Research ,Polybrominated biphenyls -- Health aspects ,Polybrominated biphenyls -- Research - Abstract
BACKGROUND: An increasing number of studies are reporting the existence of polybrominated diphenyl ethers (PBDEs) and their hydroxylated (HO) and methoxylated (MeO) metabolites in the environment and in tissues from [...]
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- 2009
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25. Association of luteinizing hormone receptor gene expression with cell cycle progression in granulosa cells
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Cannon, Jennifer D., Seekallu, Srinivas V., VandeVoort, Catherine A., and Chaffin, Charles L.
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Cell cycle -- Genetic aspects ,Cell cycle -- Research ,Gene expression -- Research ,Hormone receptors -- Physiological aspects ,Hormone receptors -- Research ,Ovaries -- Physiological aspects ,Ovaries -- Research ,Biological sciences - Abstract
During hormonally induced ovarian follicle growth, granulosa cell proliferation increases and returns to baseline prior to the administration of an ovulatory stimulus. Several key genes appear to follow a similar pattern, including the luteinizing hormone receptor (LHCGR), suggesting an association between cell cycle progression and gene expression. The expression of LHCGR mRNA in granulosa cells isolated from immature rats and treated in culture with FSH increased in a time-dependent manner, whereas administration of the cell cycle inhibitor mimosine completely suppressed expression. Although forskolin was able to induce luteinization in cells treated with mimosine, human chorionic gonadotropin had no effect, indicating the functional loss of LHCGR. The effects of mimosine on cell cycle progression and LHCGR mRNA expression were reversible within 24 h of mimosine removal. Cell cycle inhibition did not alter the stability of LHCGR mRNA, indicating that the primary effect was at the transcriptional level. To determine whether the relationship between LHCGR expression and cell cycle were relevant in vivo, immature rats were given a bolus of PMSG, followed by a second injection of either saline or PMSG 24 h later to augment levels of proliferation. The expression of LHCGR mRNA was elevated in the ovaries of animals receiving a supplement of PMSG. Mimosine also blocked cell cycle progression and LHCGR mRNA expression in macaque granulosa cells isolated following controlled ovarian stimulation cycles and in two different mouse Leydig tumor lines. These data collectively indicate that LHCGR mRNA is expressed as a function of the passage of cells across the G1-S phase boundary. granulosa cell; gene expression; ovary; proliferation
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- 2009
26. Ligand-based gene expression profiling reveals novel roles of glucocorticoid receptor in cardiac metabolism
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Yoshikawa, Noritada, Nagasaki, Masao, Sano, Motoaki, Tokudome, Satori, Ueno, Kazuko, Shimizu, Noriaki, Imoto, Seiya, Miyano, Satoru, Suematsu, Makoto, Fukuda, Keiichi, Morimoto, Chikao, and Tanaka, Hirotoshi
- Subjects
Gene expression -- Research ,Hormone receptors -- Physiological aspects ,Hormone receptors -- Research ,Heart -- Genetic aspects ,Heart -- Physiological aspects ,Heart -- Research ,Biological sciences - Abstract
Recent studies have documented various roles of adrenal corticosteroid signaling in cardiac physiology and pathophysiology. It is known that glucocorticoids and aldosterone are able to bind glucocorticoid receptor (GR) and mineralocorticoid receptor, and these ligand-receptor interactions are redundant. It, therefore, has been impossible to delineate how these nuclear receptors couple with corticosteroid ligands and differentially regulate gene expression for operation of their distinct functions in the heart. Here, to particularly define the role of GR in cardiac muscle cells, we applied a ligand-based approach involving the GR-specific agonist cortivazol (CVZ) and the GR antagonist RU-486 and performed microarray analysis using rat neonatal cardiomyocytes. We indicated that glucocorticoids appear to be a major determinant of GR-mediated gene expression when compared with aldosterone. Moreover, expression profiles of these genes highlighted numerous roles of glucocorticoids in various aspects of cardiac physiology. At first, we identified that glucocorticoids, via GR, induce mRNA and protein expression of a transcription factor Kruppel-like factor 15 and its downstream target genes, including branched-chain aminotransferase 2, a key enzyme for amino acid catabolism in the muscle. CVZ treatment or overexpression of KLF15 decreased cellular branched-chain amino acid concentrations and introduction of small-interfering RNA against KLF15 cancelled these CVZ actions in cardiomyocytes. Second, glucocorticoid-GR signaling promoted gene expression of the enzymes involved in the prostaglandin biosynthesis, including cyclooxygenase-2 and phospholipase A2 in cardiomyocytes. Together, we may conclude that GR signaling should have distinct roles for maintenance of cardiac function, for example, in amino acid catabolism and prostaglandin biosynthesis in the heart. endocrinology; cardiovascular system; KLF15; cylooxygenase-2; phospholipase A2
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- 2009
27. Androgen sensitivity of prostate epithelium is enhanced by postnatal androgen receptor inactivation
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Simanainen, Ulla, McNamara, Keely, Gao, Yan Ru, and Handelsman, David J.
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Androgens -- Physiological aspects ,Androgens -- Research ,Epithelium -- Physiological aspects ,Epithelium -- Research ,Hormone receptors -- Physiological aspects ,Hormone receptors -- Research ,Biological sciences - Abstract
Postnatal inactivation of epithelial androgen receptor (AR) in prostate epithelial AR knockout (PEARKO) mice results in hindered differentiation but enhanced proliferation of epithelial cells. As this resembles the precancerous proliferative atrophy of human prostates with undifferentiated but intensively replicating epithelial cells, we utilized the PEARKO mice to characterize the epithelial response to castration-induced involution with a focus on identifying the potential role of stromal AR and responsiveness of the androgen-deprived epithelia to the aromatizable androgen testosterone (T) or its nonaromatizable metabolite dihydrotestosterone (DHT). PEARKO and littermate control mice were orchidectomized at 8 wk of age and treated 2 wk later with subdermal implantation of 1-cm Silastic tubing filled with T or DHT for a week. Following castration, the prostatic involution and epithelial apoptosis did not significantly differ between control (intact AR) and PEARKO (only stromal AR) males, demonstrating that prostate epithelial involution following castration is mediated primarily via stromal AR-dependent apoptotic signals. Androgen replacement (T/DHT) for 7 days induced significant growth and epithelial proliferation in all prostate lobes in both control and PEARKO, but full regrowth was observed only in controls treated with T. In PEARKO, prostate androgen (T and DHT) treatment induced significant epithelial cell 'shedding' into the lumen, with T treatment resulting in acinar disorganization, cyst formation, and aberrant epithelial structures, described as a 'gland within a gland.' These data suggest that epithelial AR inactivation during postnatal prostate development sensitizes prostate epithelial cells to paracrine signaling mediated by stromal AR activity leading to indirectly androgen-induced epithelial hyperproliferation and formation of epithelial hyperplastic cysts by aromatizable androgens. gene targeting; Cre-loxP technology; genetic mouse model
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- 2009
28. Mechanical stimulus alters conformation of type 1 parathyroid hormone receptor in bone cells
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Zhang, Yan-Liang, Frangos, John A., and Chachisvilis, Mirianas
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Bone cells -- Physiological aspects ,Bone cells -- Research ,Hormone receptors -- Physiological aspects ,Hormone receptors -- Research ,Parathyroid hormone -- Physiological aspects ,Parathyroid hormone -- Research ,Biological sciences - Abstract
The molecular mechanisms by which bone cells transduce mechanical stimuli into intracellular biochemical responses have yet to be established. There is evidence that mechanical stimulation acts synergistically with parathyroid hormone PTH(1-34) in mediating bone growth. Using picosecond time-resolved fluorescence microscopy and G protein-coupled receptor conformation-sensitive fluorescence resonance energy transfer (FRET), we investigated conformational transitions in parathyroid hormone type 1 receptor (PTH1R). 1) A genetically engineered PTH1R sensor containing an intramolecular FRET pair was constructed that enabled detection of conformational activity of PTH1R in single cells. 2) The nature of ligand-dependent conformational change of PTH1R depends on the type of ligand: stimulation with the PTH(1-34) leads to conformational transitions characterized by decrease in FRET efficiency while [NH.sub.2]-terminal truncated ligand PTH(3-34) stimulates conformational transitions characterized by higher FRET efficiencies. 3) Stimulation of murine preosteoblastic cells (MC3T3-E1) with fluid shear stress (FSS) leads to significant changes in conformational equilibrium of the PTH1R in MC3T3-E1 cells, suggesting that mechanical perturbation of the plasma membrane leads to ligand-independent response of the PTH1R. Conformational transitions induced by mechanical stress were characterized by an increase in FRET efficiency, similar to those induced by the [NH.sub.2]-terminal truncated ligand PTH(3-34). The response to the FSS stimulation was inhibited in the presence of PTH(1-34) in the flow medium. These results indicate that the FSS can modulate the action of the PTH(1-34) ligand. 4) Plasma membrane fluidization using benzyl alcohol or cholesterol extraction also leads to conformational transitions characterized by increased FRET levels. We therefore suggest that PTH1R is involved in mediating primary mechanochemical signal transduction in MC3T3-E1 cells. mechanosensor; fluorescence resonance energy transfer; fluid shear stress; G protein-coupled receptor; mechanotransduction
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- 2009
29. PPAR[alpha] blocks glucocorticoid receptor [alpha]-mediated transactivation but cooperates with the activated glucocorticoid receptor [alpha] for transrepression on NF-[kappa]
- Author
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Bougarne, Nadia, Paumelle, Rejane, Caron, Sandrine, Hennuyer, Nathalie, Mansouri, Roxane, Gervois, Philippe, Staels, Bart, Haegeman, Guy, and De Bosscher, Karolien
- Subjects
Cellular signal transduction -- Research ,Cellular signal transduction -- Genetic aspects ,DNA binding proteins -- Physiological aspects ,DNA binding proteins -- Research ,Hormone receptors -- Physiological aspects ,Hormone receptors -- Genetic aspects ,Hormone receptors -- Research ,Inflammation -- Care and treatment ,Inflammation -- Research ,Science and technology - Abstract
Glucocorticoid receptor [alpha] (GR[alpha]) and peroxisome proliferator-activated receptor [alpha] (PPAR[alpha]) are transcription factors with clinically important immune-modulating properties. Either receptor can inhibit cytokine gene expression, mainly through interference with nuclear factor [kappa]B (NF-[kappa]B)-driven gene expression. The present work aimed to investigate a functional cross-talk between PPAR[alpha]- and GR[alpha]-mediated signaling pathways. Simultaneous activation of PPAR[alpha] and GR[alpha] dose-dependently enhances transrepression of NF-[kappa]B-driven gene expression and additively represses cytokine production. In sharp contrast and quite unexpectedly, PPAR[alpha] agonists inhibit the expression of classical glucocorticoid response element (GRE)-driven genes in a PPAR[alpha]-dependent manner, as demonstrated by experiments using PPAR[alpha] wild-type and knockout mice. The unclerlying mechanism for this transcriptional antagonism relies on a PPAR[alpha]-mediated interference with the recruitment of GR[alpha], and concomitantly of RNA polymerase II, to GRE-driven gene promoters. Finally, the biological relevance of this phenomenon is underscored by the observation that treatment with the PPAR[alpha] agonist fenofibrate prevents glucocorticoid-induced hyperinsulinemia of mice fed a high-fat diet. Taken together, PPAR[alpha] negatively interferes with GRE-mediated GR[alpha] activity while potentiating its antiinflammatory effects, thus providing a rationale for combination therapy in chronic inflammatory disorders. cross-talk | gluconeogenesis | inflammation | hyperinsulinema | side effects
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- 2009
30. Mineralocorticoid receptor antagonism attenuates glomerular filtration barrier remodeling in the transgenic Ren2 rat
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Whaley-Connell, Adam, Habibi, Javad, Wei, Yongzhong, Gutweiler, Alex, Jellison, Jessica, Wiedmeyer, Charles E., Ferrario, Carlos M., and Sowers, James R.
- Subjects
Angiotensin -- Physiological aspects ,Angiotensin -- Research ,Glomerular filtration rate -- Research ,Hormone receptors -- Physiological aspects ,Hormone receptors -- Research ,Biological sciences - Abstract
Recent evidence suggests that mineralocorticoid receptor (MR) antagonism has beneficial effects on tissue oxidative stress and insulin metabolic signaling as well as reducing proteinuria. However, the mechanisms by which MR antagonism corrects both renin-angiotensin-aldosterone system (RAAS) impairments in renal insulin metabolic signaling and filtration barrier/podocyte injury remain unknown. To explore this potential beneficial interactive effect of MR antagonism we used young transgenic (mRen2)27 (Ren2) rats with increased tissue RAAS activity and elevated serum aldosterone levels. Ren2 and age-matched Sprague-Dawley (SD) control rats (age 6-7 wk) were implanted with a low dose of the MR antagonist spironolactone (0.24 mg/day) or vehicle, both delivered over 21 days. Albuminuria, podocyte-specific proteins (synaptopodin, nephrin, and podocin), and ultrastructural analysis of the glomerular filtration barrier were measured in relation to RAAS activation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, reactive oxygen species (ROS), and the redox-sensitive Rho kinase (ROK). Insulin metabolic signaling was determined via measurement of insulin receptor substrate-1 (IRS-1) phosphorylation, IRS-1 ubiquitin/proteasomal degradation, and phosphorylation of Akt. Ren2 rats exhibited albuminuria, loss of podocytespecific proteins, and podocyte foot process effacement contemporaneous with reduced renal IRS-1 and protein kinase B/Akt phosphorylation compared with SD control rats (each P < 0.05). Ren2 kidneys also manifested increased NADPH oxidase/ROS/ROK in conjunction with enhanced renal tissue levels of angiotensin II (ANG II), ANG(1-12), and angiotensin type 1 receptor. Low-dose spironolactone treatment reduced albuminuria and tissue RAAS activity and improved podocyte structural and protein integrity with improvements in IRS-1/Akt phosphorylation. Thus, in this model of RAAS activation, MR antagonism attenuates glomerular/podocyte remodeling and albuminuria, in part through reductions in redox-mediated impairment of insulin metabolic signaling. renal mineralocorticoid receptor; reduced nicotinamide adenine dinucleotide phosphate oxidase; oxidative stress; podocyte
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- 2009
31. Chronic blockade of hindbrain glucocorticoid receptors reduces blood pressure responses to novel stress and attenuates adaptation to repeated stress
- Author
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Bechtold, Andrea G., Patel, Gina, Hochhaus, Guenther, and Scheuer, Deborah A.
- Subjects
Animal experimentation -- Usage ,Animal experimentation -- Methods ,Brain -- Physiological aspects ,Brain -- Research ,Corticosteroids -- Usage ,Corticosteroids -- Health aspects ,Hormone receptors -- Physiological aspects ,Hormone receptors -- Research ,Biological sciences - Abstract
Exogenous glucocorticoids act within the hindbrain to enhance the arterial pressure response to acute novel stress. Here we tested the hypothesis that endogenous glucocorticoids act at hindbrain glucocorticoid receptors (GR) to augment cardiovascular responses to restraint stress in a model of stress hyperreactivity, the borderline hypertensive rat (BHR). A 3- to 4-mg pellet of the GR antagonist mifepristone (Mif) was implanted over the dorsal hindbrain (DHB) in Wistar-Kyoto (WKY) and BHRs. Control pellets consisted of either sham DHB or subcutaneous Mif pellets. Rats were either subjected to repeated restraint stress (chronic stress) or only handled (acute stress) for 3-4 wk, then all rats were stressed on the final day of the experiment. BHR showed limited adaptation of the arterial pressure response to restraint, and DHB Mif significantly (P [less than or equal to] 0.05) attenuated the arterial pressure response to restraint in both acutely and chronically stressed BHR. In contrast, WKY exhibited a substantial adaptation of the pressure response to repeated restraint that was significantly reversed by DHB Mif. DHB Mif and chronic stress each significantly increased baseline plasma corticosterone concentration and adrenal weight and reduced the corticosterone response to stress in all rats. We conclude that endogenous corticosterone acts via hindbrain GR to enhance the arterial pressure response to stress in BHR, but to promote the adaptation of the arterial pressure response to stress in normotensive rats. Endogenous corticosterone also acts in the hindbrain to restrain corticosterone at rest but to maintain the corticosterone response to stress in both BHR and WKY rats. corticosterone; brain; nucleus of the solitary tract; hypothalamic-pituitary-adrenal axis; chronic stress
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- 2009
32. Estradiol upregulates the expression of oxytocin receptor in colon in rats
- Author
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Feng, Mei, Qin, Junfang, Wang, Chao, Ye, Yanfang, Wang, Shuanglian, Xie, Dongping, Wang, Paulus S., and Liu, Chuanyong
- Subjects
Colon (Anatomy) -- Physiological aspects ,Colon (Anatomy) -- Research ,Estradiol -- Physiological aspects ,Estradiol -- Research ,Hormone receptors -- Physiological aspects ,Hormone receptors -- Research ,Biological sciences - Abstract
The study was designed to investigate the effect of estradiol on the excitatory effect of oxytocin (OT) on colon motility. Female Wistar rats were used, and some of them were ovariectomized (OVX) and treated with vehicle or estradiol (Ez). A plastic balloon made of condom was inserted into colon to monitor the change of colonic pressure in vivo. Longitudinal muscle strips of distal colon were prepared to monitor the spontaneous contraction of colon in vitro. Expression of OT receptor (OTR) was investigated by Western blot analysis. Expression of OTR mRNA was detected by RT-PCR. Immunohistochemistry was used to locate OTR. In OVX rats, pretreatment of [E.sub.2] (4-100 [micro]g/kg sc) dose-dependently increased the excitatory effect of OT on colon motility both in vivo and in vitro and increased the expression of OTR and OTR mRNA in colon. Systemic administration of OT excited the colon motility in vivo in rats at perioda of proestrus and estrus but did not influence it at diestrus period, when the concentration of plasma [E.sub.2] was lowest in the estrous cycle. Pretreatment of atosiban, the specific OTR antagonist, and TTX, the blocker of voltage-dependent sodium channel on nerve fiber, attenuated the excitatory effect of OT on colon motility. OTR was located in myenteric plexus of colon. These results suggested that [E.sub.2] increased the excitatory effect of OT on colon motility by upregulating the expression of OTR in myenteric plexus. colon; motility
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- 2009
33. Transgenic mutant D567G but not wild-type human FSH receptor overexpression provides FSH-independent and promiscuous glycoprotein hormone Sertoli cell signaling
- Author
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Allan, Charles M., Lim, Patrick, Robson, Mathew, Spaliviero, Jenny, and Handelsman, David J.
- Subjects
Cellular signal transduction -- Research ,Gene mutations -- Health aspects ,Gene mutations -- Research ,Hormone receptors -- Physiological aspects ,Hormone receptors -- Research ,Sertoli cells -- Physiological aspects ,Sertoli cells -- Research ,Biological sciences - Abstract
We have characterized the in vivo actions of human wild-type FSH receptor (FSHR) overexpressed in Sertoli cells of transgenic (Tg) mice (TgFSHRwt) compared with transgenic overexpression of the human activated mutant FSHR*D567G (TgFSHR*D567G). Testicular TgFSHRwt expression significantly elevated specific FSH binding (>2-fold, P < 0.0 i) relative to nontransgenic testes, similar to increased FSH binding in TgFSHR*D567G testes. Isolated TgFSHRwt Sertoli cells exhibited higher FSH-stimulated cAMP levels compared with non-Tg or TgFSHR*D567G cells but did not display the elevated FSH-independent basal cAMP levels found in TgFSHR*D567G Sertoli cells. Furthermore, Sertoli cell overexpression of TgFSHR*D567G but not TgFSHRwt allowed promiscuous cAMP responses to human chorionic gonadotropin (300 IU/ml) and TSH (30 mIU/ml), demonstrating increased constitutive signaling and altered glycoprotein hormone specificity via the intracellular D567G substitution rather than FSHR overexpression. Despite elevating Sertoli cell FSH sensitivity, overexpression of TgFSHRwt had no detectable effect upon normal testis function and did not stimulate Sertoli and germ cell development in testes of gonadotropin-deficient hypogonadal (hpg) mice, in contrast to the increased meiotic and postmeiotic germ cell development in TgFSHR*D567G hpg testes. Increased steroidogenic potential of TgFSHR*D567G hpg testes was demonstrated by elevated Cypllal and Star expression, which was not detected in TgFSHRwt hpg testes. Androgen-regulated and Sertoli cell-specific Rhox5 gene expression was increased in TgFSHR*D567G but not TgFSHRwt hpg testes, providing evidence of elevated LH-independent androgen activity due to mutant FSHR*D567G. Hence, transgenic FSHR overexpression in Sertoli cells revealed that the D567G mutation confers autonomous signaling and steroidogenic activity in vivo as well as promiscuous glycoprotein hormone receptor activation, independently of FSHR overexpression alone. follicle-stimulating hormone receptor; mutation; transgenic; Sertoli cell; mouse
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- 2009
34. Prolonged RXFP1 and RXFP2 signaling can be explained by poor internalization and a lack of [beta]-arrestin recruitment
- Author
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Callander, Gabrielle E., Thomas, Walter G., and Bathgate, Ross A.D.
- Subjects
Hormone receptors -- Physiological aspects ,Hormone receptors -- Research ,Phosphorylation -- Physiological aspects ,Phosphorylation -- Research ,Relaxin -- Physiological aspects ,Relaxin -- Research ,Biological sciences - Abstract
Relaxin induces sustained physiological responses, which brings into question the deactivation processes typical of most G protein-coupled receptors (GPCR) for its receptor, relaxin family peptide receptor 1 (RXFPI). Here, we examined relaxin-dependent phosphorylation of RXFP1 and the related insulin-like peptide 3 (INSL3) receptor, RXFP2, as well as the capacity of these receptors to recruit [beta]-arrestins and internalize in response to ligand stimulation. We confirmed in human embryonic kidney (HEK)-293T cells, expressing RXFP1 or RXFP2, that both receptors elicit prolonged cAMP responses up to 6 h after stimulation. Receptors immunoprecipitated from [sup.32]P metabolically labeled cells were used to investigate the agonist-specific phosphorylation. Rapid and robust receptor phosphorylation was not observed for either RXFP1 or RXFP2, although some [sup.32]P-incorporation was observed at 30 min; however, this was not statistically significant. In accord with this result, RXFP1 and RXFP2 demonstrated poor internalization in response to relaxin or INSL3, as compared with the angiotensin II type 1 receptor ([AT.sub.1]R), which undergoes rapid and robust phosphorylation and internalization in response to angiotensin II. Additionally, coexpression of GPCR kinases has no effect on the rate of internalization for either RXFP1 or RXFP2. Confocal microscopy was used to follow the trafficking of green fluorescent proteinlabeled [beta]-arrestins after receptor activation. Neither RXFP1 nor RXFP2 activation results in recruitment of [beta]-arrestins to the cell surface, whereas [AT.sub.1]R rapidly recruits both [beta]-arrestins-1 and -2. The apparent lack of classical regulation for RXFPI and RXFP2 provides the molecular basis for the prolonged signaling and physiological actions of relaxin and related peptides. G protein-coupled receptor; relaxin; insulin-like peptide 3
- Published
- 2009
35. Dietary modulation of peroxisome proliferator-activated receptor gamma
- Author
-
Marion-Letellier, R., Dechelotte, P., Iacucci, M., and Ghosh, S.
- Subjects
Peroxisomes -- Genetic aspects ,Peroxisomes -- Properties ,Hormone receptors -- Genetic aspects ,Hormone receptors -- Properties ,Hormone receptors -- Physiological aspects ,Health - Published
- 2009
36. Growth hormone-releasing hormone as an agonist of the ghrelin receptor GHS-R1a
- Author
-
Casanueva, Felipe F., Camina, Jesus P., Carreira, Marcos C., Pazos, Yolanda, Varga, Jozsef L., and Schally, Andrew V.
- Subjects
Ghrelin -- Physiological aspects ,Hormone receptors -- Physiological aspects ,Somatotropin releasing hormone -- Physiological aspects ,Science and technology - Abstract
Ghrelin synergizes with growth hormone-releasing hormone (GHRH) to potentiate growth hormone (GH) response through a mechanism not yet fully characterized. This study was conducted to analyze the role of GHRH as a potential ligand of the ghrelin receptor, GHS-R1a. The results show that hGHRH(1-29)N[H.sub.2] (GHRH) induces a dose-dependent calcium mobilization in HEK 293 cells stably transfected with GHS-R1a an effect not observed in wild-type HEK 293 cells. This calcium rise is also observed using the GHRH receptor agonists JI-34 and JI-36. Radioligand binding and cross-linking studies revealed that calcium response to GHRH is mediated by the ghrelin receptor GHS-R1a. GHRH activates the signaling route of inositol phosphate and potentiates the maximal response to ghrelin measured in inositol phosphate turnover. The presence of GHRH increases the binding capacity of [sup.125]l-ghrelin in a dose dependent-fashion showing a positive binding cooperativity. In addition, confocal microscopy in CHO cells transfected with GHS-R1a tagged with enhanced green fluorescent protein shows that GHRH activates the GHS-R1a endocytosis. Furthermore, the selective GHRH-R antagonists, JV-1-42 and JMR-132, act also as antagonists of the ghrelin receptor GHS-R1a. Our findings suggest that GHRH interacts with ghrelin receptor GHS-R1a, and, in consequence, modifies the ghrelin-associated intracellular signaling pathway. This interaction may represent a form of regulation, which could play a putative role in the physiology of GH regulation and appetite control. Ghrelin | Ghrelin receptor | GHRH
- Published
- 2008
37. GRIP1-associated SET-domain methyltransferase in glucocorticoid receptor target gene expression
- Author
-
Chinenov, Yurii, Sacta, Maria A., Cruz, Anna R., and Rogatsky, Inez
- Subjects
Gene expression -- Research ,Hormone receptors -- Physiological aspects ,Methyltransferases -- Physiological aspects ,Science and technology - Abstract
Transcriptional regulators such as the glucocorticoid receptor (GR) recruit multiple cofactors to activate or repress transcription. Although most cofactors are intrinsically bifunctional, little is known about the molecular mechanisms dictating the specific polarity of regulation. Furthermore, chromatin modifications thought to be confined to silent loci appear in actively transcribed genes suggesting that similar enzymatic activities may mediate constitutive and transient chromatin states. GRIP1, a GR ligand-dependent coregulator of the p160 family can potentiate or inhibit transcription but the molecular contexts and mechanisms that enable GRIP1 corepressor activity are poorly understood. In a yeast 2-hybrid screen with GRIP1 repression domain (RD)-containing fragment, we repeatedly isolated the C-terminal region of a SET domain-containing protein subsequently identified as histone H4 lysine 20 trimethyltransferase, Suv4-20h1. We cloned a full-length Suv4-20h1 and dissected its interaction with GRIP1 in yeast, in vitro, and in mammalian cells. Strict nuclear localization and high salt concentration required for Suv4-20h1 extraction were consistent with its tight association with chromatin. Overexpression of Suv4-20h1 in human U2OS and A549 cells expressing integrated and endogenous GR, respectively, antagonized ligand-dependent induction of a subset of GR target genes, whereas Suv4-20h1 siRNA-mediated depletion had a reciprocal effect. Inhibition of GR transactivation required both the GRIP1 interacting region of Suv4-20h1 and its catalytic activity. Thus, Suv4-20h1 known exclusively as a factor involved in constitutive heterochromatin maintenance, actively participates in hormone-dependent transcriptional regulation affecting GR target gene expression in a promoter- and cell type-specific manner. GRIP1 cofactor | histone methyltransferase | Suv4-20h1 | transcriptional regulation
- Published
- 2008
38. The nuclear corepressor, NCoR, regulates thyroid hormone action in vivo
- Author
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Astapova, Inna, Lee, Larissa J., Morales, Crystal, Tauber, Stefanie, Bilban, Martin, and Hollenberg, Anthony N.
- Subjects
Gene expression -- Research ,Hormone receptors -- Physiological aspects ,Hormone receptors -- Genetic aspects ,Hormone receptors -- Research ,Thyroid hormones -- Physiological aspects ,Thyroid hormones -- Genetic aspects ,Thyroid hormones -- Research ,Science and technology - Abstract
The thyroid hormone receptor (TR) has been proposed to regulate expression of target genes in the absence of triiodothyronine ([T.sub.3]) through the recruitment of the corepressors, NCoR and SMRT. Thus, NCoR and SMRT may play an essential role in thyroid hormone action, although this has never been tested in vivo. To accomplish this, we developed mice that express in the liver a mutant NCoR protein (L-NCoR[DELTA]ID) that cannot interact with the TR. L-NCoR[DELTA]ID mice appear grossly normal, however, when made hypothyroid the repression of many positively regulated [T.sub.3]-target genes is abrogated, demonstrating that NCoR plays a specific and sufficient role in repression by TR in the absence of [T.sub.3]. Remarkably, in the euthyroid state, expression of many [T.sub.3]-targets is also up-regulated in L-NCoR[DELTA]ID mice, demonstrating that NCoR also determines the magnitude of the response to [T.sub.3] in euthyroid animals. Although positive [T.sub.3] targets were up-regulated in L-NCoR[DELTA]ID mice in the hypo- and euthyroid state, there was little effect seen on negatively regulated [T.sub.3] target genes. Thus, NCoR is a specific regulator of [T.sub.3]-action in vivo and mediates repression by the unliganded TR in hypothyroidism. Furthermore, NCoR appears to play a key role in determining the tissue-specific responses to similar levels of circulating [T.sub.3]. Interestingly, NCoR recruitment to LXR is also impaired in this model, leading to activation of LXR-target genes, further demonstrating that NCoR recruitment regulates multiple nuclear receptor signaling pathways. gene expression | thyroid hormone receptor
- Published
- 2008
39. Gonadotropin-releasing hormone II: a multi-purpose neuropeptide
- Author
-
Schneider, Johanna S. and Rissman, Emilie F.
- Subjects
Food habits -- Research ,Gonadotropin releasing hormone -- Physiological aspects ,Gonadotropin releasing hormone -- Genetic aspects ,Hormone receptors -- Physiological aspects ,Reproduction -- Research ,Zoology and wildlife conservation - Abstract
Close to 30 forms of gonadotropin releasing hormone (GnRH) and at least five GnRH receptors have been identified in a wide variety of vertebrates and some invertebrates. One form, now called GnRH II, has the broadest distribution and the most ancient and conserved phylogeny. The distribution of the neurons that produce this peptide are completely nonoverlapping with any other GnRH forms. Fibers that project from these neurons overlap with GnRH I cells and/or fibers in a few regions, but are primarily divergent. The musk shrew (Suncus murinus) continues to be the most tractable mammalian species to use for studies of the function of GnRH II. The brain of the musk shrew has two GnRH genes (I and II), two GnRH receptors (types-1 and -2), and two different behaviors can be influenced by central infusion of GnRH II, but not by GnRH I; receptivity and feeding. Here, we summarize research on the musk shrew relative to the behavioral functions of GnRH II. First, female musk shrews are continually sexually receptive by virtue of their lack of an ovarian and/or behavioral estrus cycle. This feature of their reproductive ecology may be related to their semi-tropical distribution and their breeding season is highly dependent on changes in the availability of food. When food is not abundant, females stop mating, but brief bouts of feeding reinstate reproductive behavior. Likewise, intake of food is related to GnRH II mRNA and peptide content in the brain; after mild food restriction both decline. When GnRH II is infused centrally, at times when its content is low, it can both enhance receptivity and inhibit food intake. Simultaneous administration of a type-1 antagonist does not change the effect of GnRH II and use of an analog (135-18) that is a specific GnRH II agonist as well as a type-1 antagonist has the same effect as the endogenous GnRH II peptide. We propose that GnRH II plays a critical role by orchestrating the coordination of reproduction with the availability of nutritional support for these activities. Humans are bombarded with copious nutritional opportunities and at present obesity is a larger threat to health in many parts of the world than is under nutrition. It is our hope that understanding neuropeptides such as GnRH II that regulate food intake can ultimately lead to products that may curb appetite and thus decrease obesity and related risks to health.
- Published
- 2008
40. The Application of an Immobilized Molecular Beacon for the Analysis of the DNA Binding Domains from the Ecdysteroid Receptor Proteins Usp and EcR's Interaction with the hsp27 Response Element
- Author
-
Krusinski, Tomasz, Laskowska, Anna, Ozyhar, Andrzej, and Dobryszycki, Piotr
- Subjects
Hormone receptors -- Measurement ,Hormone receptors -- Physiological aspects ,Hormone receptors -- Research ,Nucleic acid probes -- Usage ,Protein-protein interactions -- Measurement ,Biological sciences - Published
- 2008
41. Lack of Erectogenic Activity of a Novel Selective Melanocortin-4 Receptor Agonist in a Clinical Experimental Model
- Author
-
Krishna, Rajesh, Wong, Peggy, Stevens, Catherine, De Lepeleire, Inge, Van Dyck, Kristien, Rosen, Raymond C., Isaias, Peeters, Mathieu, Wagner, John A., and Herman, Gary A.
- Subjects
Hormone receptors -- Physiological aspects ,Hormone receptors -- Health aspects ,Impotence -- Diagnosis ,Impotence -- Care and treatment ,Health - Published
- 2008
42. Hydroxylated metabolites of the polybrominated diphenyl ether mixture de-71 are weak estrogen receptor-[alpha] ligands
- Author
-
Mercado-Feliciano, Minerva and Bigsby, Robert M.
- Subjects
Hormone receptors -- Physiological aspects ,Hormone receptors -- Research ,Metabolites -- Health aspects ,Metabolites -- Research ,Polybrominated biphenyls -- Complications and side effects ,Polybrominated biphenyls -- Environmental aspects ,Polybrominated biphenyls -- Research - Abstract
BACKGROUND: Polybrominated diphenyl ethers (PBDEs) are widely found in the environment and are suspected endocrine disruptors. We previously identified six hydroxylated metabolites of PBDE (OH-PBDEs) in treated mice. OBJECTIVE: We [...]
- Published
- 2008
43. Identification of the functional domain of thyroid hormone receptor responsible for polychlorinated biphenyl-mediated suppression of its action in vitro
- Author
-
Miyazaki, Wataru, Iwasaki, Toshiharu, Takeshita, Akira, Tohyama, Chiharu, and Koibuchi, Noriyuki
- Subjects
Binding sites (Biochemistry) -- Identification and classification ,Binding sites (Biochemistry) -- Physiological aspects ,Binding sites (Biochemistry) -- Research ,Hormone receptors -- Physiological aspects ,Hormone receptors -- Research ,Polychlorinated biphenyls -- Health aspects ,Polychlorinated biphenyls -- Environmental aspects ,Polychlorinated biphenyls -- Research - Abstract
BACKGROUND: Polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins, and poly-chlorinated dibenzofurans adversely affect the health of humans and various animals. Such effects might be partially exerted through the thyroid hormone (TH) system. [...]
- Published
- 2008
44. Effects of a high-glucose environment on the pituitary growth hormone-releasing hormone receptor: type 1 diabetes compared with in vitro glucotoxicity
- Author
-
Bedard, Karine, Strecko, Julie, Theriault, Karyne, Bedard, Julie, Veyrat-Durebex, Christelle, and Gaudreau, Pierrette
- Subjects
Blood sugar -- Physiological aspects ,Blood sugar -- Research ,Hormone receptors -- Physiological aspects ,Type 1 diabetes -- Physiological aspects ,Biological sciences - Abstract
The present study investigated the effects of diabetes and high glucose on GHRH receptor (GHRH-R) mRNA and protein levels in the pituitary of diabetic rats 2, 21, and 60 days post-streptozotocin (post-STZ) administration. Two days post-STZ, the 2.5-kb GHRH-R mRNA transcript was increased. Twenty-one days post-STZ, both the 2.5- and 4-kb transcripts and a 72-kDa [sup.125]I-GHRH-GHRH-R complex were elevated. Sixty days post-STZ, the 4-kb transcript remained increased and the 45-kDa [sup.125]I-GHRH-GHRH-R complex (functional receptor) was decreased. Hypothalamic GHRH mRNA and serum total IGF-I levels were reduced at all three time points. To better understand the role of high glucose on GHRH-R regulation, time-course effects of 33 compared with 6 mM D-glucose (DG) were examined in cultured anterior pituitary cells from 2-mo-old healthy rats. Membrane lipoperoxidation was present in 33 mM DG, and GHRH-R mRNA levels were diminished after 24 h, Fluo-GHRH internalization was marginal after 16-24 h, and GHRH-induced cAMP levels were decreased after 24 and 48 h. Altogether, these results indicate that the increase of the 2.5-kb GHRH-R mRNA transcript in vivo could be a consequence of a decrease of hypothalamic GHRH mRNA levels in STZ rats. Since it does not affect primarily functional GHRH-R levels, the initial diminution of circulating IGF-I levels could result from a decreased GHRH-R stimulation by GHRH. Thus, the effect of glucotoxicity would be related to a decrease of functional GHRH-R protein, as observed in rats 60 days post-STZ and in cultured pituitary cells from healthy rats exposed to a high-glucose environment. insulin-like growth factor I; oxidative stress; hypothalamus; cyclic adenosine monophosphate
- Published
- 2008
45. Simultaneous deletion of ghrelin and its receptor increases motor activity and energy expenditure
- Author
-
Pfluger, Paul T., Kirchner, Henriette, Gunnel, Susanne, Schrott, Brigitte, Perez-Tilve, Diego, Fu, Sheng, Benoit, Stephen C., Horvath, Tamas, Joost, Hans-Georg, Wortley, Katherine E., Sleeman, Mark W., and Tschop, Matthias H.
- Subjects
Ghrelin -- Physiological aspects ,Locomotion -- Research ,Hormone receptors -- Physiological aspects ,Biological sciences - Abstract
Administration of chemically synthesized ghrelin (Ghr) peptide has been shown to increase food intake and body adiposity in most species. However, the biological role of endogenous Ghr in the molecular control of energy metabolism is far less understood. Mice deficient for either Ghr or its receptor (the growth hormone secretagogue receptor, GHS-R1a) seem to exhibit enhanced protection against high-fat diet-induced obesity but do not show a substantial metabolic phenotype on a standard diet. Here we present the first mouse mutant lacking both Ghr and the Ghr receptor. We demonstrate that simultaneous genetic disruption of both genes of the Ghr system leads to an enhanced energy metabolism phenotype. Ghr/Ghr receptor double knockout (dKO) mice exhibit decreased body weight, increased energy expenditure, and increased motor activity on a standard diet without exposure to a high caloric environment. Mice on the same genetic background lacking either the Ghr or the Ghr receptor gene did not exhibit such a phenotype on standard chow, thereby confirming earlier reports. No differences in food intake, meal pattern, or lean mass were observed between dKO, Ghr-deficient, Ghr receptor-deficient, and wild-type (WT) control mice. Only dKO showed a slight decrease in body length. In summary, simultaneous deletion of Ghr and its receptor enhances the metabolic phenotype of single gene-deficient mice compared with WT mice, possibly suggesting the existence of additional, as of yet unknown, molecular components of the endogenous Ghr system. growth hormone secretagogue receptor, constitutive receptor activity; locomotion
- Published
- 2008
46. The effects of salt-induced hypertension on [[alpha].sub.1]-adrenoreceptor expression and cardiovascular physiology in the rainbow trout (Oncorhynchus mykiss)
- Author
-
Chen, Xi, Moon, Thomas W., Olson, Kenneth R., Dombkowski, Ryan A., and Perry, Steve F.
- Subjects
Hypertension -- Physiological aspects ,Hormone receptors -- Physiological aspects ,Cardiovascular system -- Research ,Rainbow trout -- Diseases ,Rainbow trout -- Physiological aspects ,Gene expression -- Research ,Biological sciences - Abstract
Experiments were conducted on rainbow trout to determine the impact of dietary salt on arterial blood pressure. After 4-6 wk, fish fed a salt-enriched diet exhibited a 37% elevation of dorsal aortic pressure (from 23.8 [+ or -]1.2 to 32.6 [+ or -] 1.4 mmHg) and an 18% increase in ventral aortic pressure (from 33.0 [+ or -] 1.5 to 38.9 [+ or -] 1.3 mmHg). The hypertension presumably reflected the increase in cardiac output (from 31.0 [+ or -] 0.8 to 36.4 [+ or -] 2.2 ml.[min.sup.-1]. [kg.sup.-1]) because systemic and branchial resistances were statistically unaltered by salt feeding. The chronic hypertension was associated with a decrease in the pressor responses of the systemic vasculature to catecholamines and hypercapnia in the salt-fed fish. The reduction in [alpha]-adrenergic responsiveness of the systemic vasculature is consistent with desensitization or loss of functional [alpha]-adrenoceptors ([alpha]-ARs). In support of this idea, the salt-fed fish exhibited significantly decreased levels of [[alpha].sub.1D]-AR mRNA in the dorsal aorta and the afferent (ABA) and efferent branchial arteries (EBA). In contrast, however, the results obtained from norepinephrine doseresponse curves for EBA and ABA vascular rings in vitro did not provide evidence for loss of function of branchial artery [[alpha].sub.1]-ARs in the salt-fed fish. Indeed, the [EC.sub.50] for the EBA norepinephrine doseresponse curve was significantly reduced (from 3.75 x [10.sup.-7] to 2.12 x [10.sup.-7] M) in the salt-fed fish, indicating an increase in the binding affinity of the [[alpha].sub.1]-ARs. norepinephrine; epinephrine; blood pressure; systemic resistance; salt feeding; hypercapnia; efferent branchial artery; afferent branchial artery
- Published
- 2007
47. Urocortin II mediates pro-inflammatory effects in human colonocytes via corticotropin-releasing hormone receptor 2
- Author
-
Moss, Alan C., Anton, Pauline, Savidge, Tor, Newman, Paul, Cheifetz, Adam S., Gay, Jerome, Paraschos, Sophia, Winter, Michael Weinstein, Moyer, Mary P., Karalis, Katia, Kokkotou, Efi, and Pothoulakis, Charalabos
- Subjects
Hormone receptors -- Research ,Hormone receptors -- Physiological aspects ,Neuropeptides -- Research ,Neuropeptides -- Physiological aspects ,Colitis -- Research ,Colitis -- Physiological aspects ,Health - Published
- 2007
48. Aging-related characteristics of growth hormone receptor/binding protein gene-disrupted mice
- Author
-
Coschigano, Karen T.
- Subjects
Hormone receptors -- Physiological aspects ,Hormone receptors -- Genetic aspects ,Longevity -- Genetic aspects ,Longevity -- Research ,Somatotropin -- Physiological aspects ,Somatotropin -- Genetic aspects ,Social sciences - Abstract
Byline: Karen T. Coschigano (1) Keywords: aging; gene disruption; growth hormone receptor/binding protein; longevity; mice Abstract: Since generation of the growth hormone receptor/binding protein (GHR/BP) gene-disrupted mouse nearly 10 years ago, use of this mouse model has become widespread in the elucidation of the physiological roles of GH and insulin-like growth factor-1 (IGF-1). In particular, it serves as a useful model to study mechanisms of aging. This review highlights the evidence demonstrating that the loss of GH signaling leads to lifespan extension in mice, and presents the multiple characteristics of this mouse line that suggest the life extension is due to alteration of the aging process. Author Affiliation: (1) Department of Biomedical Sciences, College of Osteopathic Medicine, Ohio University, 351 Irvine Hall, Athens, OH, 45701, USA Article History: Registration Date: 21/03/2006 Received Date: 01/11/2005 Accepted Date: 01/12/2005 Online Date: 02/06/2006
- Published
- 2006
49. Do long-lived mutant and calorie-restricted mice share common anti-aging mechanisms?--a pathological point of view
- Author
-
Ikeno, Yuji, Lew, Christie M., Cortez, Lisa A., Webb, Celeste R., Lee, Shuko, and Hubbard, Gene B.
- Subjects
Aging -- Genetic aspects ,Aging -- Research ,Hormone receptors -- Physiological aspects ,Hormone receptors -- Genetic aspects ,Low-calorie diet -- Physiological aspects ,Social sciences - Abstract
Byline: Yuji Ikeno (1,2,3), Christie M. Lew (1,2), Lisa A. Cortez (1,2), Celeste R. Webb (1,2), Shuko Lee (3), Gene B. Hubbard (4) Keywords: aging; growth hormone receptor/binding protein; knockout mouse; neoplastic disease Abstract: Rodent models are an invaluable resource for studying the mechanism of mammalian aging. In recent years, the availability of transgenic and knockout mouse models has facilitated the study of potential mechanisms of aging. Since 1996, aging studies with several long-lived mutant mice have been conducted. Studies with the long-lived mutant mice, Ames and Snell dwarf, and growth hormone receptor/binding protein knockout mice, are currently providing important clues regarding the role of the growth hormone/insulin like growth factor-1 axis in the aging process. Interestingly, these studies demonstrate that these long-lived mutant mice have physiological characteristics that are similar to the effects of calorie restriction, which has been the most effective experimental manipulation capable of extending lifespan in various species. However, a question remains to be answered: do these long-lived mutant and calorie-restricted mice extend their lifespan through a common underlying mechanism? Author Affiliation: (1) Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA (2) Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA (3) Research Service, Audie Murphy VA Hospital (STVHCS), San Antonio, TX, 78229, USA (4) Southwest National Primate Research Center, Southwest Foundation for Biomedical Research, San Antonio, TX, 78245, USA Article History: Registration Date: 21/03/2006 Received Date: 01/12/2005 Accepted Date: 15/12/2005 Online Date: 02/06/2006
- Published
- 2006
50. Determination of the energetics governing the regulatory step in growth hormone-induced receptor homodimerization
- Author
-
Bernat, Bryan, Pal, Gabor, Sun, Miao, and Kossiakoff, Anthony A.
- Subjects
Cytochemistry -- Research ,Bioenergetics -- Research ,Energy metabolism ,Somatotropin -- Physiological aspects ,Chemical reaction, Rate of -- Physiological aspects ,Gene mutations -- Physiological aspects ,Binding sites (Biochemistry) -- Research ,Cellular signal transduction -- Research ,Hormone receptors -- Physiological aspects ,Science and technology - Abstract
Signaling in the human growth hormone (hGH)-human GH receptor system is initiated by a controlled sequential two-step hormone-induced dimerization of two hGH receptors via their extracellular domains (ECDs). Little is currently known about the energetics governing the important regulatory step in receptor signaling (step 2) because of previously existing experimental barriers in characterizing the binding of the second receptor (ECD2). A further complication is that ECD2 binds through contacts from two spatially distinct sites: through its N-terminal domain to hGH, and to ECD1 through its C-terminal domain, which forms a pseudo-2-fold symmetrical interaction between the stems of the two receptors. We report here a detailed evaluation of the energetics of step 2 binding using a modified surface plasmon resonance method that is able to measure accurately the kinetics of the trimolecular binding process and separate the effects of the two binding sites. The binding kinetics of 23 single and 126 ECD1-ECD2 pair-wise alanine mutations was measured. Although both of the ECD2 binding interfaces were found to be important, the ECD1-ECD2 stem-stem contact is the stronger of the two. It was determined that most residues in the binding interfaces act in additive fashion, and that the six residues common in both ECDs contribute very differently to homodimerization depending on which ECD they reside in. This interface is characterized by a binding 'hot-spot' consisting of a core of three residues in ECD1 and two in ECD2. There is no similar hot-spot in the N-terminal domain of ECD2 binding to Site2 of hGH. This study suggests ways to engineer ECD molecules that will bind specifically to either Site1 or Site2 of hGH, providing novel reagents for biophysical and biological studies.
- Published
- 2003
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