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1.
Molecular and structural effects of inverse agonistic mutations on signaling of the thyrotropin receptor – a basally active GPCR 总被引:1,自引:0,他引:1
Kleinau G Jaeschke H Mueller S Worth CL Paschke R Krause G 《Cellular and molecular life sciences : CMLS》2008,65(22):3664-3676
Several mutations that decrease the basal signaling activity of G-protein coupled receptors (GPCRs) with pathogenic implications
are known. Here we study the molecular mechanisms responsible for this phenotype and investigate how basal and further activated
receptor conformations are interrelated. In the basally active thyroid stimulating hormone receptor (TSHR) we combined spatially-distant
mutations with opposing effects on basal activity in double-mutations and characterized mutant basal and TSH induced signaling.
Mutations lowering basal activity always have a suppressive influence on TSH induced signaling and on constitutively activating
mutations (CAMs). Our results suggest that the conformation of a basally ‘silenced’ GPCR might impair its intrinsic capacity
for signaling compared to the wild-type. Striking differences in conformation and intramolecular interactions between TSHR
models built using the crystal structures of inactive rhodopsin and partially active opsin help illuminate the molecular details
underlying mutations decreasing basal activity.
G. Kleinau, H. Jaeschke: These two authors contributed equally to this work.
Received 31 July 2008; received after revision 12 September 2008; accepted 19 September 2008 相似文献
2.
The prevalence of TSH-receptor antibodies and of thyroid autoantibodies was studied in 48 HLA-typed patients with Graves' disease, who were in an euthyroid state after antithyroid therapy with methimazole. TSH-receptor antibodies, which were found in 35% of the patients, did not correlate with the positivity of HLA B8. By contrast the persistence of thyroid microsomal antibodies was significantly associated with HLA B8. 相似文献
3.
Thyroid hormone controls carnitine status through modifications of γ-butyrobetaine hydroxylase activity and gene expression 总被引:1,自引:0,他引:1
Galland S Georges B Le Borgne F Conductier G Dias JV Demarquoy J 《Cellular and molecular life sciences : CMLS》2002,59(3):540-545
The carnitine system plays a key role in β-oxidation of long-chain fatty acids by permitting their transport into the mitochondrial
matrix. The effects of hypothyroidism and hyperthyroidism were studied on γ-butyrobetaine hydroxylase (BBH), the enzyme responsible
for carnitine biosynthesis in the rat. In rat liver, BBH activity was decreased in the hypothyroid state and increased in
hyperthyroid animals. The modifications in BBH activity correlated with changes in the enzyme Vmax values. These changes were
shown to be related to hepatic BBH mRNA abundance. Thyroid hormones are known to interact with lipid metabolism, in particular
by increasing long-chain fatty acid oxidation through activation of carnitine-dependent fatty acid import into mitochondria.
Our study showed that thyroid hormones also increased carnitine bioavailability.
Received 23 October 2001; received after revision 11 January 2002; accepted 15 January 2002 相似文献
4.
G. Schernthaner H. Ludwig H. Schleusener R. Finke P. Kotulla W. R. Mayr 《Cellular and molecular life sciences : CMLS》1979,35(10):1408-1409
Summary The prevalence of TSH-receptor antibodies and of thyroid autoantibodies was studied in 48 HLA-typed patients with Graves' disease, who were in an euthyroid state after antithyroid therapy with methimazole. TSH-receptor antibodies, which were found in 35% of the patients, did not correlate with the positivity of HLA B8. By contrast the persistence of thyroid microsomal antibodies was significantly associated with HLA B8. 相似文献
5.
F J Seif 《Experientia》1977,33(9):1243-1245
A nonlinear differential equation is used to develop a mathematical model describing the time course of thyrotropin (TSH) concentral to real data shows that pituitary responsiveness to TRH is highest in euthyroidism, reduced in primary hypothyroidism, and lowest in hyperthyroidism. 相似文献
6.
M. Slater 《Cellular and molecular life sciences : CMLS》1991,47(3):267-270
Summary Normal human autopsy anterior pituitary tissue from 5 cases was embedded in LR White resin and immunolabelled using silver-enhanced 5-nm protein A gold probes. Follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), adrenocorticotrophic hormone (ACTH), growth hormone (GH) and prolactin (PRL) were immunolocalised to the level of secretory granule.A two-sided double-labelling method was used to cross-react two hormones at a time with respect to their corresponding antibodies. All possible combinations of the six pituitary hormones were tested. Plurihormonal granules were found that contained LH+FSH, LH+TSH, and FSH+TSH. Each hormone was also found in monohormonal granules. Granule diameter was significantly larger in the pluri as opposed to monohormonal granules. 相似文献
7.
F. J. Seif 《Cellular and molecular life sciences : CMLS》1977,33(9):1243-1245
Summary A nonlinear differential equation is used to develop a mathematical model describing the time course of thyrotropin (TSH) concentration in human plasma after thyroliberin (TRH) stimulation. The application of the model to real data shows that pituitary responsiveness to TRH is highest in euthyroidism, reduced in primary hypothyroidism, and lowest in hyperthyroidism. 相似文献
8.
J. A. Fernandez-Pol J. P. Binette M. T. Hays 《Cellular and molecular life sciences : CMLS》1977,33(11):1493-1495
Summary Dog thyroid follicular cells exposed to concanavalin A (Con A) in vitro showed changes in cell shape, induction of colloid droplets and alterations in the distribution of microvilli. Cells exposed to Con A plus suboptimal concentrations of TSH (thyroid stimulating hormone) showed pseudopods and their cytoplasm was virtually occupied with colloid droplets. This findings suggest that Con A potentiated pseudopod and colloid droplet formation induced by TSH.Acknowledgments. The authors gratefully acknowledge the expert technical assistance of J. M. Greco. Supported by V. A. Research Funds. 相似文献
9.
Glutamic acid decarboxylase (GAD) is considered to be one of the strongest candidate autoantigens involved in triggering
β-cell-specific autoimmunity. The majority of recent onset type 1 diabetes patients and prediabetic subjects have anti-GAD
antibodies in their sera, as do nonobese diabetic (NOD) mice, one of the best animal models for human type 1 diabetes. Immunization
of young NOD mice with GAD results in the prevention or delay of the disease as a result of tolerizing autoreactive T cells.
Autoimmune diabetes can also be prevented by the suppression of GAD expression in antisense GAD trans genic mice backcrossed
with NOD mice for seven generations. These results support the hypothesis that GAD plays an important role in the development
of T-cell-mediated autoimmune diabetes. However, there is some controversy regarding the role of GAD in the pathogenesis of
diabetes. Whether GAD truly plays a key role in the initiation of this disease remains to be determined. The examination of
the development of insulitis and diabetes in β-cell-specific GAD knockout NOD mice will answer this remaining question.
Received 12 April 2002; received after revision 24 May 2002; accepted 27 May 2002
RID="*"
ID="*"Corresponding author. 相似文献
10.
M Slater 《Experientia》1991,47(3):267-270
Normal human autopsy anterior pituitary tissue from 5 cases was embedded in LR White resin and immunolabelled using silver-enhanced 5-nm protein A gold probes. Follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), adrenocorticotrophic hormone (ACTH), growth hormone (GH) and prolactin (PRL) were immunolocalised to the level of secretory granule. A two-sided double-labelling method was used to cross-react two hormones at a time with respect to their corresponding antibodies. All possible combinations of the six pituitary hormones were tested. Plurihormonal granules were found that contained LH + FSH, LH + TSH, and FSH + TSH. Each hormone was also found in monohormonal granules. Granule diameter was significantly larger in the pluri as opposed to monohormonal granules. 相似文献
11.
Lyme disease is a multisystem illness initiated upon infection with the spirochete Borrelia burgdorferi. Whereas the majority of patients who develop Lyme arthritis may be successfully treated with antibiotic therapy, about 10%
go on to develop arthritis which persists for months to years, despite antibiotic therapy. Development of what we have termed
treatment-resistant Lyme arthritis has previously been associated with both the presence of particular major histocompatibility
complex class II alleles and immunoreactivity to the spriochetal outer surface protein A (OspA). Recently, we showed that
patients with treatment-resistant Lyme arthritis, but not patients with other forms of arthritis, generate synovial fluid
T cell responses to an immunodominant epitope of OspA and a highly homologous region of the human-lymphocyte-function-associated
antigen-1α
L chain. Identification of a bacterial antigen capable of propagating an autoimmune response against a self-antigen provides
a model of molecular mimicry in the pathogenesis of treatment-resistant Lyme arthritis.
Received 21 December 1999; received after revision 10 April 2000; accepted 11 April 2000 相似文献
12.
Molecular basis of autosomal-dominant polycystic kidney disease 总被引:5,自引:0,他引:5
Gallagher AR Hidaka S Gretz N Witzgall R 《Cellular and molecular life sciences : CMLS》2002,59(4):682-693
Autosomal-dominant polycystic kidney disease (ADPKD) is one of the most common monogenetic diseases in humans. The discovery
that mutations in the PKD1 and PKD2 genes are responsible for ADPKD has sparked extensive research efforts into the physiological and pathogenetic role of polycystin-1
and polycystin-2, the proteins encoded by these two genes. While polycystin-1 may mediate the contact among cells or between
cells and the extracellular matrix, a lot of evidence suggests that polycystin-2 represents an endoplasmic reticulum-bound
cation channel. Cyst development has been compared to the growth of benign tumors and this view is highlighted by the model
that a somatic mutation in addition to the germline mutation is responsible for cystogenesis (two-hit model of cyst formation).
Since in vitro polycystin-1 and polycystin-2 interact through their COOH termini, the two proteins possibly act in a common
pathway, which controls the width of renal tubules. The loss of one protein may lead to a disruption of this pathway and to
the uncontrolled expansion of tubules. Our increasing knowledge of the molecular events in ADPKD has also started to be useful
in designing novel diagnostic and therapeutic strategies.
Received 12 September 2001; received after revision 7 November 2001; accepted 7 November 2001 相似文献
13.
Hepatitis C virus (HCV), a positive-sense, single-stranded RNA virus of the Flaviviridae family, is a major cause of chronic
hepatitis, liver cirrhosis, and hepatocellular carcinoma worldwide. Its RNA is difficult to study because biological materials
are scarce and RNA replication is of low efficiency. This review focuses on the structure and functions of HCV RNA along with
their biological and clinical significance. Despite the challenging characteristics of HCV, significant progress has been
made in understanding the properties of HCV RNA and developing viral replication systems toward the improvement of antiviral
therapies.
Received 15 January 2001; received after revision 2 March 2001; accepted 18 April 2001 相似文献
14.
Molina H 《Cellular and molecular life sciences : CMLS》2002,59(2):220-229
Complement has an important role in inflammation and in the normal function of the immune system. Activated complement fragments
have the capacity to bind and damage self-tissues. Cells from vertebrates express on their surface regulators of complement
activation that protect them from the deleterious effects of cell-bound complement fragments. Abnormalities in these regulators
of complement activation may participate in the pathogenesis of autoimmune diseases and inflammatory disorders. Murine Crry
is one of these regulators that inhibits the activation of the third component of complement and protects self-tissues from
complement-mediated damage. Experimental work on Crry has increased our understanding of the immunobiology of complement regulation
and the potential role of complement and complement inhibitors in the development and treatment of human diseases.
Received 13 June 2001; received after revision 12 July 2001; accepted 9 August 2001 相似文献
15.
Incorporation of E-cadherin into the adherens junction is a highly regulated process required to establish
firm cell-cell adhesion in most epithelia. Less is known about the mechanisms that govern the clearance of
E-cadherin from the cell surface in both normal and pathological states. In this study, we found that the
steady-state removal of E-cadherin in primary cultured pig thyroid cell monolayers is slow and involves
intracellular degradation. Experimental abrogation of adhesion by a Ca2+ switch induces
rapid cell surface proteolysis of E-cadherin. At the same time, endocytosed intact E-cadherin and newly
synthesized E-cadherin accumulate in intracellular compartments that largely escape further degradation. Acute
stimulation with thyroid-stimulating hormone (TSH) or forskolin prevents all signs of accelerated E-cadherin
turnover. The findings indicate that TSH receptor signaling via cyclic AMP stabilizes the assembly and retention
of E-cadherin at the cell surface. This suggests a new mechanism by which TSH supports maintenance of thyroid
follicular integrity.Received 23 February 2004; received after revision 14 May 2004; accepted 26 May 2004 相似文献
16.
Endogenous opioids have been studied extensively since their discovery, in the hope of finding a perfect analgesic, devoid
of the secondary effects of alkaloid opioids. However, the design of selective opioid agonists has proved very difficult.
First, structural studies of peptides in general are hampered by their intrinsic flexibility. Second, the relationship between
constitution and the so-called 'bioactive conformation' is far from obvious. Ideally, a direct structural study of the complex
between a peptide and its receptor should answer both questions, but such a study is not possible, because opioid receptors
are large membrane proteins, difficult to study by standard structural techniques. Thus, conformational studies of opioid
peptides are still important for drug design and also for indirect receptor mapping. This review deals with conformational
studies of natural opioid peptides in several solvents that mimic in part the different environments in which the peptides
exert their action. None of the structural investigations yields a convincing bioactive conformation, but the global conformation
of longer peptides in biomimetic environments can shed light on the interaction with receptors.
Received 15 April 2001; received after revision 10 May 2001; accepted 11 May 2001 相似文献
17.
Unraveling the pathogenesis of Parkinson’s disease – the contribution of
monogenic forms 总被引:2,自引:0,他引:2
The field of Parkinsons disease pathogenesis is rapidly evolving from the one of a monolithic and obscure entity into the one of a complex scenario with several known molecular players. The ongoing systematic exploration of the genome holds great promise for the identification of the genetic factors conferring susceptibility to the common non-Mendelian forms of this disease. However, most of the progress of the last 5 years has come from the successful mapping and cloning of genes responsible for rare Mendelian variants of Parkinsons disease. These discoveries are providing tremendous help in understanding the molecular mechanisms of this devastating disease. Here we review the genetics of the monogenic forms of Parkinsons disease. Moreover, we focus on the mechanisms of disease caused by -synuclein and parkin mutations, and the implications of this growing body of knowledge for understanding the pathogenesis of the common forms of the disease.
Received 10 March 2004; received after revision 26 April 2004; accepted 29 April 2004 相似文献
18.
The present study deals with a possible mechanism controlling the transport of manganese (Mn), an essential trace element, from the circulation to the thyroid. Mice were pretreated with propylthiouracil (PTU) or triiodothyronine (T3), and a measurement of the thyroid:serum concentration ratio (T/S) of radioactive manganese (54Mn) was carried out. The T/S of 54Mn was greatly enhanced by PTU, but reduced by T3. Several methods were used to demonstrate that the T/S of 54Mn depends upon the level of thyroid-stimulating hormone (TSH) in the serum. First, bovine TSH was injected into mice; an increase in the T/S resulted. Secondly, serum thyroxine and T3 levels measured by radioimmunoassay (RIA) suggested that PTU produced an increase in serum TSH and T3 a decrease. However, direct measurement of mouse TSH by RIA for rat TSH failed to produce proof of any changes in TSH level, owing to poor cross-reactivity. Taking all the information into account, it is concluded that Mn-transport into the thyroid is controlled by the thyroid state. 相似文献
19.
Garbern JY 《Cellular and molecular life sciences : CMLS》2007,64(1):50-65
Pelizaeus-Merzbacher disease (PMD) and the allelic spastic paraplegia type 2 (SPG2) arise from mutations in the X-linked gene
encoding myelin proteolipid protein (PLP). Analysis of mutations affecting PLP, the major protein in central nervous system
myelin, has revealed previously unsuspected roles for myelinating glia in maintaining the integrity of the nervous system.
The disease spectrum for PMD and SPG2 is extraordinarily broad and can be best understood by accounting not only for the wide
range of mutations that can occur but also for the effects of PLP1 mutations on both cell autonomous and non-cell autonomous processes in myelinating cells. Appreciating the wide range of
genetic and cellular effects of PLP1 mutations is important for patient and family counseling, understanding disease pathogenesis, and, ultimately, for developing
future disease-specific therapies.
Received 24 April 2006; received after revision 3 July 2006; accepted 9 October 2006 相似文献
20.
Protein farnesylation in mammalian cells: effects of farnesyltransferase inhibitors on cancer cells 总被引:3,自引:0,他引:3
F. Tamanoi C.-L. Gau C. Jiang H. Edamatsu J. Kato-Stankiewicz 《Cellular and molecular life sciences : CMLS》2001,58(11):1636-1649
Protein farnesylation, catalyzed by protein farnesyltransferase, plays important roles in the membrane association and protein-protein
interaction of a number of eukaryotic proteins. Recent development of farnesyltransferase inhibitors (FTIs) has led to further
insight into the biological significance of farnesylation in cancer cells. A number of reports point to the dramatic effects
FTIs exert on cancer cells. In addition to inhibiting anchorage-independent growth, FTIs cause changes in the cell cycle either
at the G1/S or at the G2/M phase. Furthermore, induction of apoptosis by FTIs has been reported. FTIs also affects the actin
cytoskeleton and cell morphology. This review summarizes these reports and discusses implications for farnesylated proteins
responsible for these FTI effects.
Received 17 April 2001; received after revision 28 May 2001; accepted 28 May 2001 相似文献