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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.
Signaling mechanisms of neurite outgrowth induced by the cell adhesion molecules NCAM and N-Cadherin
Formation of appropriate neural circuits depends on a complex interplay between extracellular guiding cues and intracellular
signaling events that result in alterations of cytoskeletal dynamics and a neurite growth response. Surface-expressed cell
adhesion molecules (CAMs) interact with the surroundings via the extracellular domain and bind to the cytoskeleton via their
intracellular domain. In addition, several CAMs induce signaling events via direct interactions with intracellular proteins
or via interactions with cell surface receptors. Thus, CAMs are obvious candidates for transmitting extracellular guidance
cues to intracellular events and thereby regulating neurite outgrowth. In this review, we focus on two CAMs, the neural cell
adhesion molecule (NCAM) and N-cadherin, and their ability to mediate signaling associated with a neurite outgrowth response.
In particular, we will focus on direct interaction between NCAM and N-cadherin with a number of intracellular partners, as
well as on their interaction with the fibroblast growth factor receptor (FGFR).
Received 23 May 2008; received after revision 14 July 2008; accepted 21 July 2008 相似文献
3.
P. J. Lardone A. Carrillo-Vico P. Molinero A. Rubio J. M. Guerrero 《Cellular and molecular life sciences : CMLS》2009,66(3):516-525
Human lymphocyte melatonin, through membrane and nuclear receptors binding, acts as an activator in IL-2 production. Antagonism
of membrane melatonin receptors using luzindole exacerbates the drop of the IL-2 production induced by PGE2 in peripheral blood mononuclear and Jurkat cells. This paper studies the melatonin membrane and nuclear receptors interplay
in PGE2-diminished IL-2 production. The decrease in IL-2 production after PGE2 and/or luzindole administration correlated with downregulation in the nuclear receptor RORα. We also highlighted a role of
cAMP in the pathway, because forskolin mimicked the effects of luzindole and/or PGE2 in the RORα expression. Finally, a significant RORα downregulation was observed in T cells permanently transfected with inducible
MT1 antisense. In conclusion, we show a novel connection between melatonin membrane receptor signalling and RORα expression,
opening a new way to understand melatonin regulation in lymphocyte physiology.
Received 23 September 2008; received after revision 19 November 2008; accepted 21 November 2008 相似文献
4.
Massicotte G 《Cellular and molecular life sciences : CMLS》2000,57(11):1542-1550
Long-term potentiation (LTP) and long-term depression (LTD) are two electrophysiological models that have been studied extensively in recent years as they may represent basic mechanisms in many neuronal networks to store certain types of information. In several brain regions, it has been shown that these two forms of synaptic plasticity require sufficient dendritic depolarization, with the amplitude of the calcium signal being crucial for the generation of either LTP or LTD. The rise in calcium concentration mediated by the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors has been proposed to stimulate various calcium-dependent enzymatic processes that could convert the induction signal into long-lasting changes in synaptic structure; protein kinases and phosphatases have so far been considered predominantly with regard to LTP and LTD formation. According to several lines of experimental evidence, changes in synaptic function observed with LTP and LTD are thought to be the result of modifications of postsynaptic currents mediated by the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamate receptors. Moreover, it has become apparent recently that activation of the calcium-dependent enzyme phospholipase A2 (PLA2) could be part of the molecular mechanisms involved in alterations of AMPA receptor properties during long-term changes in synaptic operation. In the present review, we will first describe the results that indicate a critical role of the phospholipases in regulating synaptic function. Next, sections will be devoted to the effects of PLA2 and phospholipids on the binding properties of glutamate receptors, and a revised biochemical model will be presented as an attempt to integrate the PLA2 enzyme into the mechanisms ( in particular kinases and phosphatases) that participate in adaptive neural plasticity. Finally, we will review data relevant to the issue of selective changes in AMPA binding after environmental enrichment and LTP. 相似文献
5.
Inoue K 《Cellular and molecular life sciences : CMLS》2008,65(19):3074-3080
Accumulating findings indicate that nucleotides play an important role in microglia through P2 purinoceptors. P2 purinoceptors
are divided into two families, ionotropic receptors (P2X) and metabotropic receptors (P2Y). P2X receptors (7 types; P2X1 – P2X7) contain intrinsic pores that open by binding with ATP. P2Y receptors (8 types; P2Y1, 2, 4, 6, 11, 12, 13 and 14) are activated by nucleotides and couple to intracellular second-messenger systems through heteromeric G-proteins. Nucleotides
are released or leaked from non-excitable cells as well as neurons in physiological and pathophysiological conditions. Microglia
express many types of P2 purinoceptors and are known as resident macrophages in the CNS. ATP and other nucleotides work as
‘warning molecules’ especially through activating microglia in pathophysiological conditions. Microglia play a key role in
neuropathic pain, chemotaxis and phagocytosis through nucleotide-evoked activation of P2X4, P2Y12 and P2Y6 receptors, respectively. These findings indicate that extracellular nucleotides are important players in the central stage
of microglial function.
Received 19 April 2008; received after revision 20 May 2008; accepted 23 May 2008 相似文献
6.
Bitter peptides and bitter taste receptors 总被引:1,自引:0,他引:1
Bitter peptides are a structurally diverse group of oligopeptides often generated in fermented, aged, and hydrolyzed food
products that make them unfavorable for consumption. Humans perceive bitterness by a repertoire of 25 human bitter receptors,
termed T2Rs. Knowledge of the structural features of bitter receptors and of the factors that stimulate bitter receptors will
aid in understanding the mechanism responsible for bitter taste perception. This article reviews the current knowledge regarding
structural features of bitter peptides and bitter taste receptors.
Received 24 November 2008; received after revision 11 December 2008; accepted 16 December 2008 相似文献
7.
Cellular pathology induced by snake venom phospholipase A2 myotoxins and neurotoxins: common aspects of their mechanisms of action 总被引:3,自引:0,他引:3
Montecucco C Gutiérrez JM Lomonte B 《Cellular and molecular life sciences : CMLS》2008,65(18):2897-2912
A large variety of snake toxins evolved from PLA2 digestive enzymes through a process of ‘accelerated evolution’. These toxins have different tissue targets, membrane receptors
and mechanisms of alteration of the cell plasma membrane. Two of the most commonly induced effects by venom PLA2s are neurotoxicity and myotoxicity. Here, we will discuss how these snake toxins achieve a similar cellular lesion, which
is evolutionarily highly conserved, despite the differences listed above. They cause an initial plasma membrane perturbation
which promotes a large increase of the cytosolic Ca2+ concentration leading to cell degeneration, following modes that we discuss in detail for muscle cells and for the neuromuscular
junction. The different systemic pathophysiological consequences caused by these toxins are not due to different mechanisms
of cell toxicity, but to the intrinsic anatomical and physiological properties of the targeted tissues and cells.
Received 05 March 2008; received after revision 08 April 2008; accepted 29 April 2008 相似文献
8.
Protease-activated receptors (PARs) play a clear role in the burst of inflammatory reactions and immune responses. However,
for PAR-3, the most elusive member of the PAR family, the functional role is still largely unclear. It has been claimed that
PAR-3 does not signal autonomously, although the wide expression of human PAR-3 indicates its important physiological roles.
We demonstrate that in HEK-293 cells, stably transfected with human PAR-3, thrombin induced calcium signaling, IL-8 gene expression
and IL-8 release. We confirmed this finding using human lung epithelial and human astrocytoma cells that express endogenous
PAR-3. Moreover, thrombin exposure of HEK-293 cells resulted in ERK1/2 activation coinciding with IL-8 release. The effects
of thrombin were not dependent on PAR-1 activation, as confirmed by PAR-1 gene silencing. Thus, we propose that PAR-3 is able
to signal autonomously to induce IL-8 release mediated by ERK1/2 phosphorylation, which contributes actively to inflammatory
responses.
Received 9 December 2007; received after revision 16 January 2008; accepted 18 January 2008 相似文献
9.
10.
MAGUKs in synapse assembly and function: an emerging view 总被引:4,自引:0,他引:4
Montgomery JM Zamorano PL Garner CC 《Cellular and molecular life sciences : CMLS》2004,61(7-8):911-929
11.
12.
Signaling versus punching hole: How do Bacillus thuringiensis toxins kill insect midgut cells? 总被引:1,自引:0,他引:1
Cry proteins, produced by Bacillus thuringiensis (Bt), are widely used for the control of insect pests in agriculture as spray products or expressed in transgenic crops,
such as maize and cotton. Little was known regarding the mechanism of action of these toxins when the first commercial Bt
product was introduced fifty years ago. However, research on the mechanism of action over the last two decades has enhanced
our knowledge of toxin interaction with membrane receptors and their effects in insect midgut cells. All this information
allowed for the rational design of improved toxins with higher toxicity or toxins that overcome insect resistance, which could
compromise Bt use and effectiveness in the field. In this review we discuss and evaluate the different models of the mode
of action of Cry toxins, including a discussion about the role of various receptors in toxin action.
Received 13 June 2008; received after revision 05 November 2008; accepted 11 November 2008 相似文献
13.
Cutaneous wound healing is a complex and highly coordinated process where a number of different cell types participate to
renew the damaged tissue under the strict regulation of soluble and insoluble factors. One of the most versatile processes
involved in wound repair is proteolysis. During cell migration, proteins of extracellular matrix are cleaved, often creating
biologically active cleavage products, and proteolysis of cellular contacts leads to increased cell motility and division.
Moreover, proteases activate various growth factors and other proteases in wound and regulate growth factor signaling by shedding
growth factor receptors on cell surface. Normally, proteolysis is strictly controlled, and changes in protease activity are
associated with alterations in wound closure and scar formation. Here, we present the current view on the role of metalloproteinases
and the plasmin-plasminogen system in normal and aberrant cutaneous wound repair and discuss their role as potential therapeutic
targets for chronic ulcers or fibrotic scars.
Received 07 July 2008; received after revision 11 August 2008; accepted 13 August 2008 相似文献
14.
Light-harvesting complexes of vascular plants 总被引:1,自引:0,他引:1
Schmid VH 《Cellular and molecular life sciences : CMLS》2008,65(22):3619-3639
Light-harvesting complexes (LHCs) located in the thylakoid membrane of plant chloroplasts are the collectors of solar radiation
that fuel photosynthesis, and thus enable life on our planet. They consist of pigments that are non-covalently bound to light-harvesting
proteins (Lhc proteins), which form a family whose members share a significant sequence identity. Due to their central role
in photosynthesis, LHCs belong in several respects to the best-analysed membrane proteins. In the past decade, tremendous
progress has been made in identifying new members of the Lhc family, in localising the LHCs within the photosystems, and in
elucidating the structure and function of LHCs, which is summarised in this review. By contrast, gaining insight into the
assembly process and the degradation of the LHCs could not keep pace. Therefore, topics for the next decade will be the elucidation
of the location(s) and the operating mode of steps in the assembly and degradation process.
Received 15 June 2008; received after revision 1 July 2008; accepted 10 July 2008 相似文献
15.
Tang M Zhong M Shang Y Lin H Deng J Jiang H Lu H Zhang Y Zhang W 《Cellular and molecular life sciences : CMLS》2008,65(18):2924-2932
Advanced glycation end products (AGEs) play an important role in collagen deposition in diabetic cardiomyopathy. TRB3, a mammalian
homolog of Drosophila tribbles, functions to increase glucose intolerance and regulates cell proliferation. We demonstrated
that AGEs induce collagen type I expression but inhibit collagen type III expression, accompanied by increased TRB3 expression.
Furthermore, the collagen type I induced byAGEs was down-regulated after inhibition of ERK and p38-MAPK, the collagen type
III reduced by AGEs was up-regulated after inhibition of ERK. The expression of collagen types I and III regulated by AGEs
through MAPK was partly reversed after treatment with TRB3 siRNA. It suggests that the TRB3/MAPK signaling pathway participates
in the regulation of collagen types I and III by AGEs and may provide new therapeutic strategies for diabetic cardiomyopathy.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
Received 08 May 2008; received after revision 25 June 2008; accepted 22 July 2008
M. Tang, M. Zhong: These two authors contributed equally to this work. 相似文献
16.
Nicotinic acetylcholine receptors (nAChRs) exist in many subtypes and are found in the peripheral and central nervous system
where they mediate or modulate synaptic transmission. We review how tyrosine phosphorylation and kinases regulate muscle and
neuronal nAChRs. Interestingly, although some of the same kinase players interact with the various receptor subtypes, the
functional consequences are different. While concerted action of MuSK, Abl- and Src-family kinases (SFKs) regulates the synaptic
distribution of nAChRs at the neuromuscular junction, SFKs activate heteromeric neuronal nAChRs in adrenal chromaffin cells,
thereby enhancing catecholamine secretion. In contrast, the activity of homomeric neuronal nAChRs, as found in the hippocampus,
is negatively regulated by tyrosine phosphorylation and SFKs. It appears that tyrosine kinases provide the means to regulate
all nAChRs; but the functional consequences, even those caused by the same kinase family, are specific for each receptor subtype
and location.
Received 21 February 2006; received after revision 24 July 2006; accepted 30 August 2006 相似文献
17.
C. L. Salanga M. O’Hayre T. Handel 《Cellular and molecular life sciences : CMLS》2009,66(8):1370-1386
Chemokines are small, secreted proteins that bind to the chemokine receptor subfamily of class A G protein-coupled receptors.
Collectively, these receptor-ligand pairs are responsible for diverse physiological responses including immune cell trafficking,
development and mitogenic signaling, both in the context of homeostasis and disease. However, chemokines and their receptors
are not isolated entities, but instead function in complex networks involving homo- and heterodimer formation as well as crosstalk
with other signaling complexes. Here the functional consequences of chemokine receptor activity, from the perspective of both
direct physical associations with other receptors and indirect crosstalk with orthogonal signaling pathways, are reviewed.
Modulation of chemokine receptor activity through these mechanisms has significant implications in physiological and pathological
processes, as well as drug discovery and drug efficacy. The integration of signals downstream of chemokine and other receptors
will be key to understanding how cells fine-tune their response to a variety of stimuli, including therapeutics.
Received 19 October 2008; received after revision 7 November 2008; accepted 11 November 2008
C. L. Salanga, M. O’Hayre: These authors contributed equally. 相似文献
18.
Over the last few years remarkable efforts have been made using functional imaging studies to unravel brain processing of
pain and decipher underlying neuronal mechanisms. Cerebral processing in experimental pain models, especially those provoking
hyperalgesia, and its pharmacological modulation will form the first part of this review. In a second part we will address
central mechanisms of clinical neuropathic pain. Up to now, there are at least six main mechanisms involved in the chronification
of neuropathic pain: (i) activity increase in areas of the pain neuromatrix, (ii) recruitment of additional cortical areas
beyond the classical pain neuromatrix, (iii) cortical reorganization and maladaptive neuroplasticity, (iv) alterations in
neurochemistry (v) structural brain changes and (vi) disruption of the brain default mode network. In a third part of this
review we discuss mechanisms of endogenous pain modulation.
Received 22 July 2008; received after revision 26 August 2008; accepted 2 September 2008 相似文献
19.
Small conductance calcium-activated potassium (SK or KCa2) channels link intracellular calcium transients to membrane potential changes. SK channel subtypes present different pharmacology
and distribution in the nervous system. The selective blocker apamin, SK enhancers and mice lacking specific SK channel subunits
have revealed multifaceted functions of these channels in neurons, glia and cerebral blood vessels. SK channels regulate neuronal
firing by contributing to the afterhyperpolarization following action potentials and mediating IAHP, and partake in a calcium-mediated feedback loop with NMDA receptors, controlling the threshold for induction of hippocampal
long-term potentiation. The function of distinct SK channel subtypes in different neurons often results from their specific
coupling to different calcium sources. The prominent role of SK channels in the modulation of excitability and synaptic function
of limbic, dopaminergic and cerebellar neurons hints at their possible involvement in neuronal dysfunction, either as part
of the causal mechanism or as potential therapeutic targets.
Received 23 April 2008; received after revision 29 May 2008; accepted 4 June 2008 相似文献
20.
S. M. Houten M. Chegary H. te Brinke W. J. Wijnen J. F. C. Glatz J. J. F. P. Luiken F. A. Wijburg R. J. A. Wanders 《Cellular and molecular life sciences : CMLS》2009,66(7):1283-1294
Organs are flexible as to which substrates they will use to maintain energy homeostasis. Under well-fed conditions, glucose
is a preferred substrate for oxidation. During fasting, fatty acid oxidation will become a more important energy source. Glucose
oxidation is decreased by fatty acids, a process in which the pyruvate dehydrogenase complex (PDH) and its regulator pyruvate
dehydrogenase kinase 4 (PDK4) play important roles. It is currently unknown how energy status influences PDH activity. We
show that AMP-activated protein kinase (AMPK) activation by hypoxia and AICAR treatment combined with fatty acid administration
synergistically induce PDK4 expression. We provide evidence that AMPK activation modulates ligand-dependent activation of
peroxisome proliferator-activated receptor. Finally, we show that this synergistic induction of PDK4 decreases cellular glucose
oxidation. In conclusion, AMPK and fatty acids play a direct role in fuel selection in response to cellular energy status
in order to spare glucose.
S. M. Houten, M. Chegary: These two authors contributed equally to this work.
Received 11 July 2008; received after revision 26 January 2009; accepted 02 February 2009 相似文献