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)

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)

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)

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)

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.

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)

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)

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)

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)

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)

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)

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)

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)

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 MT1and MT2, which are expressed in many different organs and tissues. Understanding the pharmacology and function of mouse MT1and (...) MT2receptors, including MT1/MT2heteromers, 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)

Primary cilia are singular projections that extend from the surface of most vertebrate cell types. The surface area of the primary cilium (PC) is estimated to represent only 1/100th of the total membrane surface of an average cell. Despite this, the PC provides essential contributions to inter‐ and intracellular communication by housing receptors and downstream effectors for myriad cell‐signaling cascades. G protein‐coupled receptors (GPCRs) commonly enrich along ciliary membranes to control a diverse range of cellular behaviors by signaling through a (...) shared pool of downstream effectors. This suggests the hypothesis that the PC provides an environment that is conducive to complementary or competitive GPCR Signal Crosstalk. In this Hypothesis Bio Essay, we use the Sonic Hedgehog (SHH) pathway as a case study to inform models of how GPCR signals could intersect in primary cilia and suggest general strategies to test each model. (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)

In this article, onset mechanisms of colorectal cancer and intestinal bowel diseases (IBD) are postulated to involve the aberrant expression/hyper‐activation of E‐type prostanoid 4 (EP4) receptors. Although prostaglandin E2 and EP4 receptors are important factors for maintaining colorectal homeostasis, their mediated signaling is also considered to be involved in the etiology of severe intestinal diseases. To prevent uncontrollable activations of EP4 receptors, two safety factors are proposed: butyrate as an external safety factor and interleukin (IL)‐4 as an internal safety factor. (...) Thus, for maintaining vulnerable colorectal homeostasis, the levels of EP4 receptors, butyrate, and IL‐4 are proposed as an important triad for protecting against development/onset risks of, at least, EP4 receptor‐mediated cancer and IBD. (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)

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.

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)

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)

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)

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)

Signal transduction via receptors for N‐formylmethionyl peptide chemoattractants (FPR) on human neutrophils is a highly regulated process which involves participation of cytoskeletal elements. Evidence exists suggesting that the cytoskeleton and/or the membrane skeleton controls the distribution of FPR in the plane of the plasma membrane, thus controlling the accessibility of FPR to different proteins in functionally distinct domains. In desensitized cells, FPR are restricted to domains which are depleted of G proteins but enriched in cytoskeletal proteins such as actin and (...) fodrin. Thus, the G protein signal transduction partners of FPR become inaccessible to the agonist‐occupied receptor, preventing cell activation. The mechanism of interaction of FPR with the membrane skeleton is poorly understood but evidence is accumulating that suggests a direct binding of FPR (and other receptors) to cytoskeletal proteins such as actin. (shrink)

A distinct group of receptors including DCC, UNC5, RET and Ptc1 is known to function in ligand‐dependent neuronal growth and differentiation or axon guidance. Acting as “dependence receptors”, they may also regulate neuronal cell survival by inducing apoptosis in the absence of cognate ligand. Receptor‐initiated apoptosis requires proteolytic (caspase) cleavage and exposure of a pro‐apoptotic region in the cytoplasmic domains of the receptors. In contrast, classical apoptosis induced by growth factor or cytokine deprivation involves loss of survival signaling without (...) receptor cleavage. DCC, UNC5, RET and Ptc1 are downregulated or mutated in diverse cancers, and show properties characteristic of tumor suppressors, consistent with their ability to promote neuronal cell death. Dysfunctional dependence receptors have been linked to the loss of specific neurons in certain inherited and neurodegenerative diseases. Dependence receptor‐initiated apoptosis represents a novel paradigm for the controlled removal of specific cells during neural development and elimination of malignant cells that have strayed beyond regions of ligand availability. BioEssays 26:656–664, 2004. © 2004 Wiley Periodicals, Inc. (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)

Trypanosoma brucei is the causal agent of African Trypanosomiasis in humans and other animals. It maintains a long‐term infection through an antigenic variation based population survival strategy. To proliferate in a mammal, T. brucei acquires iron and haem through the receptor mediated uptake of host transferrin and haptoglobin‐hemoglobin respectively. The receptors are exposed to host antibodies but this does not lead to clearance of the infection. Here we discuss how the trypanosome avoids this fate in the context of recent (...) findings on the structure and cell biology of the receptors. (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)

It was, until recently, accepted that the two classes of acetylcholine (ACh) receptors are distinct in an important sense: muscarinic ACh receptors signal via heterotrimeric GTP binding proteins (G proteins), whereas nicotinic ACh receptors (nAChRs) open to allow flux of Na+, Ca2+, and K+ ions into the cell after activation. Here we present evidence of direct coupling between G proteins and nAChRs in neurons. Based on proteomic, biophysical, and functional evidence, we hypothesize that binding to G proteins modulates the activity (...) and signaling of nAChRs in cells. It is important to note that while this hypothesis is new for the nAChR, it is consistent with known interactions between G proteins and structurally related ligand‐gated ion channels. Therefore, it underscores an evolutionarily conserved metabotropic mechanism of G protein signaling via nAChR channels.Also watch the Video Abstract. (shrink)

I present here a personal perspective on more than three decades of research into the structural biology of the insulin–receptor interaction. The solution of the three‐dimensional structure of insulin in 1969 provided a detailed understanding of the insulin surfaces involved in self‐assembly. In subsequent years, hundreds of insulin analogues were prepared by insulin chemists and molecular biologists, with the goal of relating the structure to the biological function of the molecule. The design of methods for direct receptor‐binding studies (...) in the 1970s, and the cloning of the receptor in the mid 1980s, provided the required tools for detailed structure–function studies. In the absence of a full three‐dimensional structure of the insulin–receptor complex, I attempt to assemble the existing pieces of the puzzle generated by our and other laboratories, in order to generate a plausible mechanistic model of the insulin–receptor interaction that explains its kinetics and negative cooperativity. BioEssays 26:1351–1362, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Wnt signaling plays pivotal roles during our entire lives, from conception to death, through the regulation of morphogenesis in developing embryos and the maintenance of tissue homeostasis in adults. The regulation of Wnt signaling occurs on several levels: at the receptor level on the plasma membrane, at the β‐catenin protein level in the cytoplasm, and through transcriptional regulation in the nucleus. Several recent studies have focused on the mechanisms of Wnt receptor regulation, following the discovery that the Wnt (...) receptor frizzled (Fzd) is a target of the ubiquitin ligases, RNF43 and ZNRF3. RNF43 and ZNRF3 are homologous genes that are mutated in several cancers. The details underlying their mechanism of action continue to unfold, while at the same time raising many new questions. In this review, we discuss advances and controversies in our understanding of Wnt receptor regulation. (shrink)

Rare copy number variants have a prominent role in the aetiology of schizophrenia and other neuropsychiatric disorders. Substantial risk for schizophrenia is conferred by large CNVs at several loci, including microdeletions at 1q21.1, 3q29, 15q13.3 and 22q11.2 and microduplication at 16p11.2. However, these CNVs collectively account for a small fraction of cases, and the relevant genes and neurobiological mechanisms are not well understood. Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of copy (...) number gains at chromosome 7q36.3 with schizophrenia. Microduplications with variable breakpoints occurred within a 362-kilobase region and were detected in 29 of 8,290 patients versus 2 of 7,431 controls in the combined sample. All duplications overlapped or were located within 89 kilobases upstream of the vasoactive intestinal peptide receptor gene VIPR2. VIPR2 transcription and cyclic-AMP signalling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered vasoactive intestinal peptide signalling in the pathogenesis of schizophrenia and indicate the VPAC2 receptor as a potential target for the development of new antipsychotic drugs. © 2011 Macmillan Publishers Limited. All rights reserved. (shrink)

Deciphering how DCAFs (DDB1‐CUL4 Associated Factors) modulate a broad spectrum of cellular processes, including cell cycle progression and maintenance of genomic integrity is critical to better understand cellular homeostasis and diseases. Cells contain more than 100 DCAFs that associate with the Cullin‐Ring Ubiquitin Ligase 4 (CRL4) complex that target specific protein substrates for degradation. DCAFs are thought to act as substrate receptors that dictate the specificity of the ubiquitination machinery (“catalytic DCAFs”). However, recent studies have suggested that some DCAFs might (...) play a different role by targeting CRL4 complexes to distinct cellular compartments (“structural DCAFs”). Once localized to their correct cellular domains, these CRLs dissociate from the structural DCAFs prior to their association with other, substrate‐specific catalytic DCAFs. Thus, we propose that DCAF switches can provide a mechanistic basis for the degradation of proteins that regulate cell growth and proliferation at precise points in space and time. (shrink)