The glucocorticoid receptor belongs to an important class of transcription factors that alter the expression of target genes in response to a specific hormone signal. The glucocorticoid receptor can function at least at three levels: (1) recruitment of the general transcription machinery; (2) modulation of transcription factor action, independent of DNA binding, through direct protein‐protein interactions; and (3) modulation of chromatin structure to allow the assembly of other gene regulatory proteins and/or the general transcription machinery on (...) the DNA. This review will focus on the multifaceted nature of protein‐protein interactions involving the glucocorticoid receptor and basal transcription factors, coactivators and other transcription factors, occurring at these different levels of regulation. (shrink)

Glucocorticoid hormones are effective in controlling inflammation, but the mechanisms that confer this action are largely unknown. Recent advances in this field have shown that both positive and negative regulation of gene expression are necessary for this process. The genes whose activity are modulated in the anti‐inflammatory process code for several cytokines, adhesion molecules and enzymes. Most of them do not carry a classical binding site for regulation by a glucocorticoid receptor, but have instead regulatory sequences for (...) transcription factors such as AP‐1 or NF‐κ. This makes them unusual targets for glucocorticoid action and emphasizes the need for novel regulatory mechanisms. Recent studies describe an important contribution by protein‐protein interactions, in which several domains of the receptor participate; these studies provide a better understanding of the action of the receptor and offer opportunities for the design of steroidal compounds that could function more effectively as anti‐inflammatory drugs. (shrink)

Sex steroids, through their receptors, have potent effects on the signal pathways involved in osteogenic or myogenic differentiation. However, a considerable segment of those signal pathways has a prominent role in epithelial neoplastic transformation. The capability to intervene locally has focused on specific ligands for the receptors. Nevertheless, many signals are mapped to interactions of steroid receptor motifs with heterologous regulatory proteins. Some of those proteins interact with the glucocorticoid receptor and other factors essential to cell fate. (...) Interactions of steroid receptor domain motifs with heterologous proteins affect specific target pathways; consequently, manipulation of specified protein modules complexed with steroid receptors may be a next major step for enhancing molecular targeted therapeutics. In the future, intervention at specific sections of receptor primary sequence may prove therapeutically more efficient in targeting pathways of choice than ligand selectivity can be. (shrink)

While outcomes for children with T-cell acute lymphoblastic leukemia have improved dramatically, survival rates for patients with relapsed/refractory disease remain dismal. Prior studies indicate that glucocorticoid resistance is more common than resistance to other chemotherapies at relapse. In addition, failure to clear peripheral blasts during a prednisone prophase correlates with an elevated risk of relapse in newly diagnosed patients. Here we show that intrinsic GC resistance is present at diagnosis in early thymic precursor T-ALLs as well as in a (...) subset of non-ETP T-ALLs. GC-resistant non-ETP T-ALLs are characterized by strong induction of JAK/STAT signaling in response to interleukin-7 stimulation. Removing IL7 or inhibiting JAK/STAT signaling sensitizes these T-ALLs, and a subset of ETP T-ALLs, to GCs. The combination of the GC dexamethasone and the JAK1/2 inhibitor ruxolitinib altered the balance between pro- and anti-apoptotic factors in samples with IL7-dependent GC resistance, but not in samples with IL7-independent GC resistance. Together, these data suggest that the addition of ruxolitinib or other inhibitors of IL7 receptor/JAK/STAT signaling may enhance the efficacy of GCs in a biologically defined subset of T-ALL.Leukemia advance online publication, 30 May 2017; doi:10.1038/leu.2017.136. (shrink)

Alpha‐fetoprotein (AFP)AFP, alpha‐fetoprotein; T3R, thyroid hormone (triiodothyronine) receptor; RAR, retionic acid receptor; erbA, putative thyroid hormone receptor proto‐oncogene products; VDR, vitamin D receptor; MR, mineralocorticoid receptor; GR, glucocorticoid receptor; PR, progesterone receptor; AR, androgen receptor; HRE, hormone response element on DNA; RXR, retionic‐X‐receptor; RAP, receptor auxiliary (accessory) proteins; E, estrogen. is a tumor‐associated fetal marker, associated both with tumor growth and with birth defects. AFP, whose precise function is unknown, (...) has been classified as belonging to a protein superfamily together with albumin and vitamin D‐binding (Gc) protein. AFP has been shown to bind various ligands in vitro including fatty acids, estrogens, thyroid hormones and retinoic acids. The steroid/thyroid nuclear receptor superfamily of proteins has recently become a major focus of biomedical investigation regarding regulation of gene expression. These receptors are thought to bind to DNA‐hormone response elements (HRE) that affect growth, development, differentiation, reproduction and homeostasis. The HREs are known to share DNA sequences with the various members of the nuclear receptor superfamily. In the present report, the possibility of a leucine‐zipper dimerization (heptad) motif in the carboxy‐terminal third domain of both rodent and human AFP is postulated. The presence of nine such hydrophobic repeats in the third domain of the AFP molecule mimics the heptad dimerization repeats found in the retinoic acid, thyroid, e‐erbA and other members of the nuclear receptor superfamily. Computer analysis revealed that the most conservative matching occurred between AFP and the retinoic acid class of receptors. However, other superfamily members displayed 40–60% homology with 5 of 9 AFP heptads. These findings could provide a possible mechanism for explaining the growth‐regulatory properties (both inhibition and enhancement) that have been ascribed to AFP in the last decade. (shrink)

Retinoids play an important role in development and differentiation(1,2). Their effect is mediated through nuclear receptors, RAR (α, β and γ) and RXR (α, β and γ),Abbreviations. RAR: retinoic acid receptor; RXR: retinoid X receptor; T3:thyroid hormone receptor; VD3R: vitamin D3 receptor; PPAR: peroxisome proliferator activated receptor; EcR ecdycsone receptor; USP, ultraspiracle; NGFI‐B: also referred to as nur77a; ELP: embryonal long terminal repeat‐binding protein; FTZ‐F1: positive regulator of the fushi tarazu gene in blastodermstage embryos (...) of Drosophila melanogaster; GR: glucocorticoid receptor; ER: estrogen receptor; RARE, retinoic acid response element; PR: progesterone receptor; DR+x: direct repeat with a spacing of x nucleotides; DBD: DNA‐binding domain; CRABP I and II: cellular retinoic acid binding protein type I and II, respectively; MoMLV: Moloney Murine Leukemia Virus; TBP: TATA‐binding protein; TAF: TBP associated factor. which are members of a distinct subclass (hereafter referred to as type II) of the nuclear receptor superfamily that includes the thyroid hormone receptor (T3R), the vitamin D3 receptor (VD3R) and the peroxisome proliferator activated receptor (PPAR). Type II receptors transactivate through binding sites composed of closely related half‐sites (consensus sequence AGG/T TCA) arranged as direct repeats and, with the possible exception of RXR, do not bind to their cognate binding sites as homodimers but require RXR for high affinity binding. RXR thus provides a link between biologically distinct ligand induced pathways and is a potential target for cross‐regulation. In addition, RAR can utilize alternative routes to enhance transcription initiation mediated through transcriptional co‐activators which are expressed in a cell‐type specific manner. (shrink)

Transcription factor (TF) signaling regulates gene transcription and requires a complex network of proteins. This network includes co‐activators, co‐repressors, multiple TFs, histone‐modifying complexes, and the basal transcription machinery. It has been widely appreciated that pioneer factors, such as FoxA1 and GATA1, play an important role in opening closed chromatin regions, thereby allowing binding of a secondary factor. In this review we will focus on a newly proposed model wherein multiple TFs, such as steroid receptors (SRs), can function in a pioneering (...) role. This model, termed dynamic assisted loading, integrates data from widely divergent methodologies, including genome wide ChIP‐Seq, digital genomic footprinting, DHS‐Seq, live cell protein dynamics, and biochemical studies of ATP‐dependent remodeling complexes, to present a real time view of TF chromatin interactions. Under this view, many TFs can act as initiating factors for chromatin landscape programming. Furthermore, enhancer and promoter states are more accurately described as energy‐dependent, non‐equilibrium steady states. (shrink)

With aging, incidence of severe stress‐related diseases increases. However, mechanisms, underlying individual vulnerability to stress and age‐related diseases are not clear. The goal of this review is to analyze finding from the recent literature on age‐related characteristics of the hypothalamic‐pituitary‐adrenal (HPA) axis associated with stress reactivity in animals that show behavioral signs of anxiety and depression under mild stress, and in human patients with anxiety disorders and depression with emphasis on the impact of the circadian rhythm and the negative feedback (...) mechanisms involved in the stress response. One can conclude that HPA axis reaction to psycho‐emotional stress, at least acute stress, increases in the aged individuals with anxiety and depression behavior. Elevated stress reactivity is associated with disruption of the circadian rhythm and the mineralocorticoid receptor‐mediated glucocorticoid negative feedback. The disordered function of the HPA axis in individuals with anxiety and depression behavior can contribute to aging‐related pathology. (shrink)

In human languages, a palindrome reads the same forward as backward (e.g., ‘madam’). In regulatory DNA, a palindrome is an inverted sequence repeat that allows a transcription factor to bind as a homodimer or as a heterodimer with another type of transcription factor. Regulatory palindromes are typically imperfect, that is, the repeated sequences differ in at least one base pair, but the functional significance of this asymmetry remains poorly understood. Here, we review the use of imperfect palindromes in Drosophila photoreceptor (...) differentiation and mammalian steroid receptor signaling. Moreover, we discuss mechanistic explanations for the predominance of imperfect palindromes over perfect palindromes in these two gene regulatory contexts. Lastly, we propose to elucidate whether specific imperfectly palindromic variants have specific regulatory functions in steroid receptor signaling and whether such variants can help predict transcriptional outcomes as well as the response of individual patients to drug treatments. (shrink)

Various explanations have been proposed to account for complex differentiation and development in humans, despite the human genome containing only two to three times the number of genes in invertebrates. Ignored are the actions of adrenal and sex steroids—androgens, estrogens, glucocorticoids, mineralocorticoids, and progestins—which act through receptors that arose from an ancestral nuclear receptor in a protochordate. This ligand‐based mechanism is unique to vertebrates and was integrated into the already robust network of transcription factors in invertebrates. Adrenal and sex (...) steroids influence almost all aspects of vertebrate differentiation and development. I propose that evolution of this ligand‐based mechanism in a primitive vertebrate was an important contribution to vertebrate complexity. Sequencing of genomes from a cephalochordate, such as amphioxus, and from hagfish and lamprey will establish early events in the evolution of steroid hormone signaling, and also allow genetic studies to elucidate how vertebrate complexity depends on steroid hormones. BioEssays 25:396–400, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

An extensive, and controversial, literature concluding that prolactin (PRL), growth hormone (GH), insulin-like growth factor-I (IGF-I), and thyroid hormones are critical immunoregulatory factors has accumulated. However, recent studies of mice deficient in the production of these hormones or expression of their receptors indicate that there are only a few instances in which these hormones are required for lymphocyte development or antigen responsiveness. Instead, a case is made that their primary role is to counteract the effects of negative immunoregulatory factors, such (...) as glucocorticoids, which are produced when the organism is subjected to major stressors. The immunoprotective actions of PRL, GH, IGF-I, and/or thyroid hormones in these instances may ensure immune system homeostasis and reduce the susceptibility to stress-induced disease. These immuno-enhancing effects could be exploited clinically in instances where the immune system is depressed due to illness or various treatment regimens. BioEssays 23:288–294, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

The power of the application of bioinformatics across multiple publicly available transcriptomic data sets was explored. Using 19 human and mouse circadian transcriptomic data sets, we found that NR1D1 and NR1D2 which encode heme‐responsive nuclear receptors are the most rhythmic transcripts across sleep conditions and tissues suggesting that they are at the core of circadian rhythm generation. Analyzes of human transcriptomic data show that a core set of transcripts related to processes including immune function, glucocorticoid signalling, and lipid metabolism (...) is rhythmically expressed independently of the sleep‐wake cycle. We also identify key transcripts associated with transcription and translation that are disrupted by sleep manipulations, and through network analysis identify putative mechanisms underlying the adverse health outcomes associated with sleep disruption, such as diabetes and cancer. Comparative bioinformatics applied to existing and future data sets will be a powerful tool for the identification of core circadian‐ and sleep‐dependent molecules. (shrink)

The majority of G protein-coupled receptors (GPCRs) self-assemble in the form dimeric/oligomeric complexes along the plasma membrane. Due to the molecular interactions they participate, GPCRs can potentially provide the framework for discriminating a wide variety of intercellular signals, as based on some kind of combinatorial receptor codes. GPCRs can in fact transduce signals from the external milieu by modifying the activity of such intracellular proteins as adenylyl cyclases, phospholipases and ion channels via interactions with specific G-proteins. However, in spite (...) of the number of cell functions they can actually control, both GPCRs and their associated signal transduction pathways are extremely well conserved, for only a few alleles with null or minor functional alterations have so far been found. This would seem to suggest that, beside a mechanism for DNA repairing, there must be another level of quality control that may help maintaining GPCRs rather stable throughout evolution. We propose here receptor oligomerization to be a basic molecular mechanism controlling GPCRs redundancy in many different cell types, and the plasma membrane as the first hierarchical cell structure at which selective categorical sensing may occur. Categorical sensing can be seen as the cellular capacity for identifying and ordering complex patterns of mixed signals out of a contextual matrix, i.e., the recognition of meaningful patterns out of ubiquitous signals. In this context, redundancy and degeneracy may appear as the required feature to integrate the cell system into functional units of progressively higher hierarchical levels. (shrink)

Estrogen receptor α (ERα) is a ligand‐dependent transcription factor that regulates the expression of estrogen‐responsive genes. Approximately 70% of patients with breast cancer are ERα positive. Estrogen stimulates cancer cell proliferation and contributes to tumor progression. Endocrine therapies, which suppress the ERα signaling pathway, significantly improve the prognosis of patients with breast cancer. However, the development of de novo or acquired endocrine therapy resistance remains a barrier to breast cancer treatment. Therefore, understanding the regulatory mechanisms of ERα is essential (...) to overcome the resistance to treatment. This review focuses on the regulation of ERα expression, including copy number variation, epigenetic regulation, transcriptional regulation, and stability, as well as functions from the point of view post‐translational modifications. (shrink)

Progress in solving the structure of insulin bound to its receptor has been slow and stepwise, but a milestone has now been reached with a refined structure of a complex of insulin with a “microreceptor” that contains the primary binding site. The insulin receptor is a dimeric allosteric enzyme that belongs to the family of receptor tyrosine kinases. The insulin binding process is complex and exhibits negative cooperativity. Biochemical evidence suggested that insulin, through two distinct binding sites, (...) crosslinks two receptor sites located on each α subunit. The structure of the unliganded receptor ectodomain showed a symmetrical folded‐over conformation with an antiparallel disposition. Further work resolved the detailed structure of receptor site 1, both without and with insulin. Recently, a missing piece in the puzzle was added: the C‐terminal portion of insulin's B‐chain known to be critical for binding and negative cooperativity. Here I discuss these findings and their implications. (shrink)

Certain steroids can react with proteins to form stable, covalent addition products. 16α‐hydroxyestrone and the glucocorticoids, for example, contain ketol moieties which permit them to react non‐enzymatically with proteins by forming Schiffbase rearrangement products with lysine residues. The oral contraceptive agent, 17α‐ethinylestradiol, can add to proteins after being enzymatically activated by microsomal oxidation. Elevated plasma levels of these steroids result in an increased amount of protein modification in vivo. Recent investigations have linked the occurrence of steroid‐modified proteins with pathological sequelae (...) associated with high steroid levels. (shrink)

Nuclear pore complexes mediate and control transport between the cytosol and the nucleus. They form a highly selective and, thus, tight nuclear barrier between these compartments. The nuclear barrier provides the cell with the opportunity to control access to its DNA, a defining feature of eukaryotes. The tightness of the nuclear barrier is therefore physiologically pivotal and any remarkable change in its structure and permeability can prove pathophysiological, e.g. as a result of viral attack. However, there is accumulating evidence that (...) nuclear barrier structure and permeability are highly responsive to hydrophobic cargos of crucial physiological and therapeutic relevance, glucocorticoids (steroid hormones). The present review highlights the glucocorticoid‐induced effects on the nuclear barrier structure and permeability concluding that they are physiologically essential to mediate glucocorticoid action. BioEssays 28: 935–942, 2006. © 2006 Wiley periodicals, Inc. (shrink)

The Protein Ontology provides terms for and supports annotation of species-specific protein complexes in an ontology framework that relates them both to their components and to species-independent families of complexes. Comprehensive curation of experimentally known forms and annotations thereof is expected to expose discrepancies, differences, and gaps in our knowledge. We have annotated the early events of innate immune signaling mediated by Toll-Like Receptor 3 and 4 complexes in human, mouse, and chicken. The resulting ontology and annotation data set (...) has allowed us to identify species-specific gaps in experimental data and possible functional differences between species, and to employ inferred structural and functional relationships to suggest plausible resolutions of these discrepancies and gaps. (shrink)

How different neural crest derivatives differentiate in distinct embryonic locations in the vertebrate embryo is an intriguing issue. Many attempts have been made to understand the underlying mechanism of specific pathway choices made by migrating neural crest cells. In this speculative review we suggest a new mechanism for the regulation of neural crest cell migration patterns in avian and mammalian embryos, based on recent progress in understanding the expression and activity of receptor tyrosine kinases during embryogenesis. Distinct subpopulations of (...) crest‐derived cells express specific receptor tyrosine kinases while residing in a migration staging area. We postulate that the differential expression of receptor tyrosine kinases by specific subpopulations of neural crest cells allows them to respond to localized growth factor ligand activity in the embryo. Thus, the migration pathway taken by neural crest subpopulations is determined by their receptor tyrosine kinase response to the differential localization of their cognate ligand. (shrink)

Plasma membranes are subject to continuous deformations. Strikingly, some of these transient membrane undulations yield membrane‐associated signaling hubs that differ in composition and function, depending on membrane geometry and the availability of co‐factors. Here, recent advancements on this ubiquitous type of receptor‐independent signaling are reviewed, with a special focus on emerging concepts and technical challenges associated with studying these elusive signaling sites.

We propose that the primary cause of schizophrenia is a pathological extension of synaptic pruning involving local connectivity that unfolds ordinarily during adolescence. Computer simulations suggest that this pathology provides reasonable accounts of a range of symptoms in schizophrenia, and is consistent with recent postmortem and genetic studies. NMDA-receptors play a regulatory role in maintaining and/or eliminating cortical synapses, and therefore may play a pathophysiological role.

Christians working cross-culturally to bring about change in other societies desire to conduct their interventions ethically. What seems ethical and endorsed by God from the donor's point of view, however, may not be perceived as ethical in terms of the cultural values of the receptors. The nature of this problem is discussed and guidelines suggested to assist us in recognizing and overcoming the problem. The primary guideline in the application of the Golden Rule in terms of the culturally conditioned perception (...) of the receptors. (shrink)

We agree with Shors & Matzel's general hypothesis that the proposed link between NMDA-dependent LTP and memory is weak. They suggest that NMDA-dependent LTP is important to arousal or attentional processes which influence learning in an anterograde manner. However, current evidence is also consistent with the view that NMDA receptors modulate memory consolidation retroactively, as occurs in several other receptor classes.

Oligodendrocytes are known to express Ca2+-permeable glutamate receptors and to have low resistance to oxidative stress, two factors that make them potentially susceptible to injury. Oligodendrocyte injury is intrinsic to the loss of function experienced in conditions ranging from cerebral palsy to spinal cord injury, focal ischaemia and multiple sclerosis. NMDA receptors, a subtype of glutamate receptors, are vital to the remodeling of synaptic connections during postnatal development and associative learning abilities in adults and possibly in improvements in oligodendrocyte function. (...) Previous studies had failed to detect NMDA receptor mRNA or current in oligodendrocytes but three new papers1-3 demonstrate NMDA receptor expression in oligodendrocytes and discuss its implications for ischaemia therapy. BioEssays 28: 460–464, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Meeting humans is an everyday experience for most companion dogs, and their behavior in these situations and its genetic background is of major interest. Previous research in our laboratory reported that in German shepherd dogs the lack of G allele, and in Border collies the lack of A allele, of the oxytocin receptor gene (OXTR) 19208A/G single nucleotide polymorphism (SNP) was linked to increased friendliness, which suggests that although broad traits are affected by genetic variability, the specific links between (...) alleles and behavioural variables might be breed-specific. In the current study, we found that Siberian huskies with the A allele approached a friendly unfamiliar woman less frequently in a greeting test, which indicates that certain polymorphisms are related to human directed behaviour, but that the relationship patterns between polymorphisms and behavioural phenotypes differ between populations. This finding was further supported by our next investigation. According to primate studies, endogenous opioid peptide (e.g. endorphins) receptor genes have also been implicated in social relationships. Therefore, we examined the rs21912990 of the OPRM1 gene. Firstly, we found that the allele frequencies of Siberian huskies and gray wolves were similar, but differed from that of Border collies and German shepherd dogs, which might reflect their genetic relationship. Secondly, we detected significant associations between the OPRM1 SNP and greeting behaviour among German shepherd dogs and a trend in Border collies, but we could not detect an association in Siberian huskies. Although our results with OXTR and OPRM1 gene variants should be regarded as preliminary due to the relatively low sample size, they suggest that (1) OXTR and OPRM1 gene variants in dogs affect human-directed social behaviour and (2) their effects differ between breeds. (shrink)

Unraveling the molecular detail of insulin receptor activation has proved challenging, but a major advance is the recent determination of crystallographic structures of insulin in complex with its primary binding site on the receptor. The current model for insulin receptor activation is that two distinct surfaces of insulin monomer engage sequentially with two distinct binding sites on the extracellular surface of the insulin receptor, which is itself a disulfide‐linked (αβ)2 homodimer. In the process, conformational changes occur (...) both within the hormone and the receptor, the latter resulting in the disruption of the intracellular interactions that hold the kinase domains in their basal state and in the initiation of the phosphorylation events that drive insulin signaling. The purpose of this paper is to summarize the extant structural data relating to hormone binding and how it effects receptor activation, as well as to discuss the issues that remain unresolved. (shrink)

Recent findings necessitate revision of the traditional view of G protein‐coupled receptor (GPCR) signaling and expand the diversity of mechanisms by which receptor signaling influences cell behavior in general. GPCRs elicit signals at the plasma membrane and are then rapidly removed from the cell surface by endocytosis. Internalization of GPCRs has long been thought to serve as a mechanism to terminate the production of second messengers such as cAMP. However, recent studies show that internalized GPCRs can continue to (...) either stimulate or inhibit cAMP production in a sustained manner. They do so by remaining associated with their cognate G protein subunit and adenylyl cyclase at endosomal compartments. Once internalized, the GPCRs produce cellular responses distinct from those elicited at the cell surface. (shrink)

Glucagon-like peptide-1 (GLP-1) receptor agonists, such as semaglutide, and dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists, such as tirzepatide, have been found to be effective for treating obesity and diabetes, significantly reducing weight and the risk or predicted risk of adverse cardiovascular events. There is a global shortage of these medications that could last several years and raises questions about how limited supplies should be allocated. We propose a fair-allocation framework that enables evaluation of the ethics (...) of current practices and could guide governments, professional societies, and physicians in allocation decisions. (shrink)

Molecular vibrations and quantum tunneling may link ligand binding to the function of pharmacological receptors. The well‐established lock‐and‐key model explains a ligand's binding and recognition by a receptor; however, a general mechanism by which receptors translate binding into activation, inactivation, or modulation remains elusive. The Vibration Theory of Olfaction was proposed in the 1930s to explain this subset of receptor‐mediated phenomena by correlating odorant molecular vibrations to smell, but a mechanism was lacking. In the 1990s, inelastic electron tunneling (...) was proposed as a plausible mechanism for translating molecular vibration to odorant physiology. More recently, studies of ligands’ vibrational spectra and the use of deuterated ligand analogs have provided helpful information to study this admittedly controversial hypothesis in metabotropic receptors other than olfactory receptors. In the present work, based in part on published experiments from our laboratory using planarians as an experimental organism, I will present a rationale and possible experimental approach for extending this idea to ligand‐gated ion channels. (shrink)

The Hippo pathway, a cascade of protein kinases that inhibits the oncogenic transcriptional coactivators YAP and TAZ, was discovered in Drosophila as a major determinant of organ size in development. Known modes of regulation involve surface proteins that mediate cell‐cell contact or determine epithelial cell polarity which, in a tissue‐specific manner, use intracellular complexes containing FERM domain and actin‐binding proteins to modulate the kinase activities or directly sequester YAP. Unexpectedly, recent work demonstrates that GPCRs, especially those signaling through Galpha12/13 such (...) as the protease activated receptor PAR1, cause potent YAP dephosphorylation and activation. This response requires active RhoA GTPase and increased assembly of filamentous (F‐)actin. Morever, cell architectures that promote F‐actin assembly per se also activate YAP by kinase‐dependent and independent mechanisms. These findings unveil the ability of GPCRs to activate the YAP oncogene through a newly recognized signaling function of the actin cytoskeleton, likely to be especially important for normal and cancerous stem cells. (shrink)

A model of an intentional self-observing system is proposed based on the structure and functions of astrocyte-synapse interactions in tripartite synapses. Astrocyte-synapse interactions are cyclically organized and operate via feedforward and feedback mechanisms, formally described by proemial counting. Synaptic, extrasynaptic and astrocyte receptors are interpreted as places with the same or different quality of information processing described by the combinatorics of tritograms. It is hypothesized that receptors on the astrocytic membrane may embody intentional programs that select corresponding synaptic and extrasynaptic (...) receptors for the formation of receptor-receptor complexes. Basically, the act of self-observation is generated if the actual environmental information is appropriate to the intended observation processed by receptor-receptor complexes. This mechanism is implemented for a robot brain enabling the robot to experience environmental information as “its own”. It is suggested that this mechanism enables the robot to generate matches and mismatches between intended observations and the observations in the environment, based on the cyclic organization of the mechanism. In exploring an unknown environment the robot may stepwise construct an observation space, stored in memory, commanded and controlled by the intentional self-observing system. Finally, the role of self-observation in machine consciousness is shortly discussed. (shrink)

Melatonin, the neuro‐hormone synthesized during the night, has recently seen an unexpected extension of its functional implications toward type 2 diabetes development, visual functions, sleep disturbances, and depression. Transgenic mouse models were instrumental for the establishment of the link between melatonin and these major human diseases. Most of the actions of melatonin are mediated by two types of G protein‐coupled receptors, named MT1 and MT2, which are expressed in many different organs and tissues. Understanding the pharmacology and function of mouse (...) MT1 and MT2 receptors, including MT1/MT2 heteromers, will be of crucial importance to evaluate the relevance of these mouse models for future therapeutic developments. This review will critically discuss these aspects, and give some perspectives including the generation of new mouse models. (shrink)

This study examines the family environments and hormone profiles of 316 individuals aged 2 months-58 years residing in a rural village on the east coast of Dominica, a former British colony in the West Indies. Fieldwork was conducted over an eight-year period (1988–1995). Research methods and techniques include radioimmunoassay of cortisol and testosterone from saliva samples (N=22,340), residence histories, behavioral observations of family interactions, extensive ethnographic interview and participant observation, psychological questionnaires, and medical examinations.Analyses of data indicate complex, sex-specific effects (...) of family environment on endocrine function. Male endocrine profiles exhibit greater sensitivity to presence of father than do female endocrine profiles. Father-absent males tend to have (a) low cortisol levels during infancy, (b) high or abnormal cortisol profiles during childhood and adolescence, and (c) high cortisol and low testosterone levels during adulthood compared with those of males raised with a resident father. These results indicate that early family environment has significant effects on endocrine response throughout male life histories. (shrink)

Receptor oligomerization plays a key role in maintaining genome stability and restricting protein mutagenesis. When properly folded, protein monomers assemble as oligomeric receptors and interact with environmental ligands. In a gene-centered view, the ligand specificity expressed by these receptors is assumed to be causally predetermined by the cell genome. However, this mechanism does not fully explain how differentiated cells have come to express specific receptor repertoires and which combinatorial codes have been explored to activate their associated signaling pathways. (...) It is our contention that the plasma membrane acts as the locus where several contextual cues may be integrated. As such it allows the semiotic selection of those receptor configurations that provide cells with the minimum essential requirements for agency. The occurrence of protein misfolding makes it impossible for receptor monomers to assemble along the membrane and to sustain meaningful relationships with environmental ligands. How could a cell lineage deal with these loss-of-function mutations during evolution and restrain gene redundancy accordingly? In this paper, we will be arguing that the easiest way for bacteria clones to accomplish this goal is by getting rid of cells expressing mutated receptor proteins. The mechanism sustaining this cell selection is also occurring in many somatic tissues and its function is currently believed to counteract in vivo protein mutagenesis. Our discussion will be mainly focused on the significance and semiotic nature of the interplay between membrane receptors and the epigenetic control of gene expression, as mediated by the control of mismatched repairing and protein folding mechanisms. (shrink)

Receptors on cytotoxic T lymphocytes and natural killer cells play well‐established roles in the immunological response and share a common ligand in the form of MHC‐I. We discuss how a variety of MHC‐I receptors are also expressed on myelomonocytic cells such as macrophages and dendritic cells. Since myelomonocytic MHC‐I receptors recognise a broad range of alleles and MHC‐I structures, we propose that their task is to discern expression levels and folding forms of MHC. We describe a model in which these (...) recognition events would regulate bidirectional cross talk between cells of innate and adaptive immune systems to organise an ongoing combined immune response. We discuss how such a model is supported by recent literature and might function in a variety of contexts, including immunoregulation during pregnancy. Our model also offers an alternative explanation of immune dysregulation rather than autoimmunity during HLA‐B27‐associated spondyloarthropathies and addresses a number of conundrums in this field. BioEssays 27: 542–550, 2005. © 2005 Wiley periodicals, Inc. (shrink)

Receptor‐mediated endocytosis occurs via clathrin‐coated pits and is therefore coupled to the dynamic cycle of assembly and disassembly of the coat constituents. These coat proteins comprise part, but certainly not all, of the machinery involved in the recognition of membrane receptors and their selective packaging into transport vesicles for internalization. Despite considerable knowledge about the biochemistry of coated vesicles and purified coat proteins, little is known about the mechanisms of coated pit assembly, receptor‐sorting and coated vesicle formation. Cell‐free (...) assays which faithfully reconstitute these events provide powerful new tools with which to elucidate the overall mechanism of receptor‐mediated endocytosis. (shrink)

CB1 receptors are functionally present within brain mitochondria, although they are usually considered specifically targeted to plasma membrane. Acute activation of mtCB1 alters mitochondrial ATP generation, synaptic transmission, and memory performance. However, the detailed mechanism linking disrupted mitochondrial metabolism and synaptic transmission is still uncharacterized. CB1 receptors are among the most abundant G protein-coupled receptors in the brain and impact on several processes, including fear coping, anxiety, stress, learning, and memory. Mitochondria perform several key physiological processes for neuronal homeostasis, including (...) production of ATP and reactive oxygen species, calcium buffering, metabolism of neurotransmitters, and apoptosis. It is therefore possible that acute activation of mtCB1 impacts on these different mitochondrial functions to modulate synaptic transmission. In reviewing and integrating across the literature in this area, we describe the possible mechanisms involved in the regulation of brain physiology by mtCB1 receptors. Activation of mitochondrial CB1 but not of plasma membrane CB1 decreases brain mitochondrial activity, glutamatergic synaptic transmission, and memory performance. Several processes can be involved in this alteration of brain physiology, including mitochondrial ATP and ROS production, axonal mitochondrial transport, Ca2+ homeostasis, and/or metabolism of the neurotransmitter glutamate. (shrink)

Disorders of consciousness (DoC)—that is, unresponsive wakefulness syndrome/vegetative state and minimally conscious state—are debilitating conditions for which no reliable markers of consciousness recovery have yet been identified. Evidence points to the GABAergic system being altered in DoC, making it a potential target as such a marker.

SUR2, similar to SUR1, is a regulatory subunit of the ATP‐sensitive potassium channel (KATP), which plays a key role in numerous important physiological processes and is implicated in various diseases. Recent structural studies have revealed that, like SUR1, SUR2 can undergo ligand‐dependent dynamic conformational changes, transitioning between an inhibitory inward‐facing conformation and an activating occluded conformation. In addition, SUR2 possesses a unique inhibitory Regulatory helix (R helix) that is absent in SUR1. The binding of the activating Mg‐ADP to NBD2 of (...) SUR2 competes with the inhibitory Mg‐ATP, thereby promoting the release of the R helix and initiating the activation process. Moreover, the signal generated by Mg‐ADP binding to NBD2 might be directly transmitted to the TMD of SUR2, prior to NBD dimerization. Furthermore, the C‐terminal 42 residues (C42) of SUR2 might allosterically regulate the kinetics of Mg‐nucleotide binding on NBD2. These distinctive properties render SUR2 intricate sensors for intracellular Mg‐nucleotides. (shrink)

Any living organism interacts with and responds specifically to environmental molecules by expressing specific olfactory receptors. In this paper, this specificity will be first examined in causal terms with particular emphasis on the mechanisms controlling olfactory gene expression, cell-to-cell interactions and odor-decoding processes. However, this type of explanation does not entirely justify the role olfactory receptors have played during evolution, since they are also expressed ectopically in different organs and/or tissues. Homologous olfactory genes have in fact been found in such (...) diverse cells and/or organs as spermatozoa, testis and kidney where they are assumed to act as chemotactic sensors or renin modulators. To justify their functional diversity, homologous olfactory receptors are assumed to share the same basic role: that of conferring a self-identity to cells or tissues under varying environmental conditions. By adopting this standpoint, the functional attribution as olfactory or chemotactic sensors to these receptors should not be seen either as a cause conditioning receptor gene expression, or as a final effect resulting from genetically predetermined programs, but as a direct consequence of the environmental conditions olfactory receptor genes have explored during evolution. The association of odorant patterns with specific environmental or contextual situations makes their relationship semiotically triadic, due to the emergence of an interpretant capable of perceiving odorants as meaningful signs out of a noisy background. This perspective highlights the importance of odorant-receptor relationships as respect to the properties of the interacting partners. It is our contention that only when taken together can these different explanatory strategies provide a realistic account of how olfactory receptor genes have been structurally and functionally modified during evolution. (shrink)

Biological macromolecules, considered as the items of the biochemical domain, are typically conceived under the ontological category of substantial individuals. In this paper, I will argue that the philosophical framework of process ontology, according to which the living world is not populated by individuals but by a dynamic hierarchy of processes, is more adequate to account for the structure and functioning of macromolecules. In particular, I will analyze its application to the phenomenon of cell signaling and to one of its (...) key concepts, cell receptors. Current knowledge in biochemistry allows us to conceive receptors as processual and dynamic entities, relationally stabilized and not separated from the biochemical phenomenon of which they are part. (shrink)

Steroid hormone receptors are ligand‐inducible transcription factors that exhibit potent effects on gene expression in living cells. Precise dissection of their mode of action at the molecular level can best be carried out in functional cell‐free systems. This article will describe the benefits of such systems and review their development up to the recent establishment of steroid receptor‐dependent in vitro transcription. Subsequent advances in our knowledge of receptor function arising from the exploitation of this powerful experimental tool will (...) be described. Particular emphasis will be placed upon two key problems: the role of steroid hormone in receptor action and the mechanisms by which steroid receptors activate gene transcription. (shrink)

Urokinase and its receptor are essential components of the cell migration machinery, providing an inducible, transient and localized cell surface proteolytic activity. This activity has been shown to be required in normal and pathological forms of cellular invasiveness (i.e. in several embryonic developmental processes, during inflammatory responses and cancer metastasis and spreading). It represents one of the best known of the protcolytic systems which are currently under investigation in this field. The urokinase receptor allows a continuous regulation of (...) the proteolytic activity at cell contacts, utilizing the different localization of urokinase and its inhibitors. The receptor, in fact, in addition to focusing the enzymatic activity at focal and cell‐cell contacts, also regulates it by internalizing and degrading only the inhibited form of urokinase. Internalized receptor releases the ligands to the lysosomes and recycles back to surface. In this way, the proteolytically active areas of the cell surface can be continuously monitored for their activity and their location modified. The cell can thus coordinate its migration efforts with a step‐wise modification of the proteolytic activity‐map of the cell surface. The urokinase cycle can be supported by one individual cell (autocrine) or by two or more cells. In the latter case, complementation and synergism of urokinase and its receptor are found. (shrink)