Evaluation of rage isoforms, ligands, and signaling in the brain

Since the identification of the receptor for advanced glycosylation end products (RAGE) in 1992, there have been tremendous strides made in our understanding of the role RAGE receptors play in a variety of physiological and pathological processes. Despite such progress, several fundamental aspects of RAGE expression and RAGE function remain largely unanswered. In particular, while multiple forms of the RAGE receptor are known to exist, little is known with regards to how these different isoforms of the RAGE receptor work together to mediate RAGE signaling. For example, some forms of the RAGE receptor may promote deleterious feed-forward pathways, while others may serve to inhibit deleterious activation of the RAGE receptor. Additionally, important questions remain with regards to the intracellular domain of the full-length RAGE receptor, and the specifics surrounding how intracellular signaling pathways become activated via the RAGE family of receptors. The focus of this review is to address each of these important issues, as well as other key aspects of RAGE biology, and discuss how they are important for both our understanding of the physiological and pathological roles of RAGE signaling within the brain.     

The multi-functional role of sphingosylphosphorylcholine

The sphingomyelin metabolite, sphingosylphosphorylcholine (SPC) has been the subject of much recent interest and controversy. Studies have indicated that SPC naturally occurs in plasma and a constituent of lipoproteins. Synthesis is also increased in some pathological conditions. Research has demonstrated that SPC is a potentially important lipid mediator of cell type specific functions in major tissues, such as heart, blood vessels, skin, brain and immune system. These effects are regulated via a number of different intracellular signalling cascades, also dependent upon cell type. Initial reports identifying high affinity SPC receptors at first appeared to reinforce the physiological relevance of this sphingolipid. However, these studies have now been retracted. Some SPC effects have been shown be occur via plasma membrane receptors for the related sphingolipid, sphingosine 1-phosphate (S1P). Despite a lack of well-defined receptor signal transduction mechanisms and sparse pharmacological data, several key characteristics of SPC are now emerging. SPC can act as a mitogen in several different cell types and in certain circumstances, may also be a pro-inflammatory mediator. In this review, these actions of SPC are discussed with a view to understanding the potential physiological relevance of this sphingolipid.     

Cholesterol and caveolae: structural and functional relationships

Caveolae are free cholesterol (FC)- and sphingolipid-rich surface microdomains abundant in most peripheral cells. Caveolin, a FC binding protein, is a major structural element of these domains. Caveolae serve as portals to regulate cellular FC homeostasis, possibly via their association with ancillary proteins including scavenger receptor B1. The FC content of caveolae regulates the transmission of both extracellular receptor-mediated and endogenous signal transduction via changes in the composition of caveolin-associated complexes of signaling intermediates. By controlling surface FC content, reporting membrane changes by signal transduction to the nucleus, and regulating signal traffic in response to extracellular stimuli, caveolae exert a multifaceted influence on cell physiology including growth and cell division, adhesion, and hormonal response. Cell surface lipid 'rafts' may assume many of the functions of caveolae in cells with low levels of caveolin.     

Partial adenosine A1 receptor agonists for cardiovascular therapies

Extracellular purines and pyrimidines have emerged as key regulators of a wide range of physiological and pathophysiological cellular processes acting through P1 and P2 cell surface receptors. Increasing evidence suggests that purinergic receptors can interact with and/or modulate the activity of other classes of receptors and ion channels. This review will focus on the interactions of purinergic receptors with other GPCRs, ion channels, receptor tyrosine kinases, and steroid hormone receptors. Also, the signal transduction pathways regulated by these complexes and their new functional properties are discussed.     

Alternative dimerization of receptor tyrosine kinases with signal transduction through a cellular membrane

Receptor tyrosine kinases (RTKs) occupy a separate functional niche among membrane receptors, which is determined by the special features of mechanisms of the signal transduction through a cellular membrane. RTKs are involved in the regulation of development and homeostasis of all the tissues of a human organism, playing a central role in cell proliferation, differentiation, and adhesion. A necessary condition of the biochemical signal transduction through a plasmatic membrane is a ligand-dependent or a ligand-independent dimerization (and/or an oligomerization) of RTKs which is accompanied by conformational rearrangements of all the RTK domains, including the α-helical transmembrane segments. In this review, the main aspects of structure-function relationship for RTKs from various receptor subfamilies are briefly discussed. It is shown in the light of the recently obtained biophysical and biochemical data that functioning of RTK receptors is mediated not only by protein–protein interactions, but by the state of the lipid environment as one of the main components of a self-consistent signal transduction system as well. The new principles of intercellular signal transduction through a membrane replenish the molecular mechanisms of the RTK functioning that have been earlier proposed and explain a number of paradoxes which are observed upon activation of wild-type receptors and the receptors with pathogenic transmembrane mutations. Understanding of the complex mechanisms of the signaling processes can facilitate the successful search for new opportunities of influence on the RTK biological functions with potential therapeutic consequences.     

Dopamine D1–D2 receptor heterodimers: A literature review

The review summarizes current literature data on the structure of heteromeric complexes of dopamine receptors and their possible role in physiological and pathological processes in the brain. It includes analysis of studies on dopamine D1–D2 receptor complexes, their localization in the brain and the functional role. Functionally, these receptor complexes employ a principally different pathway of signal transduction as compared to the parent homomeric receptors. Investigation of dopamine receptor heteromers extends our understanding of the mechanisms of ligand-receptor interaction and opens new opportunities for the development of pharmacological agents for the treatment of psychiatric disorders associated with impaired dopaminergic neurotransmission, particularly, drug dependence.     

A mechanistic role for polypeptide hormone receptor lateral mobility in signal transduction

Summary Lateral diffusion of membrane-integral receptors within the plane of the membrane has been postulated to be mechanistically important for signal transduction. Direct measurement of polypeptide hormone receptor lateral mobility using fluorescence photobleaching recovery techniques indicates that tyrosine kinase receptors are largely immobile at physiological temperatures. This is presumably due to their signal transduction mechanism which requires intermolecular autophosphorylation through receptor dimerization and thus immobilization for activation. In contrast, G-protein coupled receptors must interact with other membrane components to effect signal transduction, and consistent with this, the phospholipase C-activating vasopressin V₁- and adenylate cyclase activating V₂-receptors are highly laterally mobile at 37°C. Modulation of the V₂-receptor mobile fraction (f) has demonstrated a direct correlation between f and receptor-agonist-dependent maximal cAMP productionin vivo at 37°C. This indicates that f is a key parameter in hormone signal transduction especially at physiological hormone concentrations, consistent with mobile receptors being required to effect V₂-agonist-dependent activation of G-proteins. Measurements using a V₂-specific antagonist show that antagonist-occupied receptors are highly mobile at 37°C, indicating that receptor immobilization is not the basis of antagonism. In contrast to agonist-occupied receptor however, antagonistoccupied receptors are not immobilized prior to endocytosis and down-regulation. Receptors may thus be freely mobile in the absence of agonistic ligand; stimulation by hormone agonist results in receptor association with other proteins, probably including cytoskeletal components, and immobilization. Receptor immobilization may be one of the important steps of desensitization subsequent to agonistic stimulation, through terminating receptor lateral movement which is instrumental in generating and amplifying the initial stimulatory signal within the plane of the membrane.Abbreviations FBR fluorescence photobleaching recovery - EGF epidermal growth factor - AC adenylate cyclase - D apparent lateral diffusion coefficient - f mobile fraction - G- GTP-binding protein - Gs stimulatory G-protein - TKR tyrosine kinase receptor - PDGF platelet-derived growth factor - IL interleukin     

RGMb/DRAGON与BMP信号转导

RGMb/DRAGON为RGM家族成员之一,在许多组织和器官中存在并表达.最初它作为粘附分子在神经系统中调节轴突排斥被发现.近来研究发现,它还是BMP的辅助受体,与BMP配体和受体结合,通过调控BMP信号通路在繁殖、肾脏机能的维持以及免疫疾病等生理和病理条件下发挥重要作用.本文评述了RGMb的基因及蛋白结构特征、表达定位及其在神经系统中的作用,并重点介绍了其在BMP信号通路中的作用机制和生物学研究进展.     

Structural basis for the regulation of phytohormone receptors

Phytohormones are central players in diverse plant physiological events, such as plant growth, development, and environmental stress and defense responses. The elucidation of their regulatory mechanisms through phytohormone receptors could facilitate the generation of transgenic crops with cultivation advantages and the rational design of growth control chemicals. During the last decade, accumulated structural data on phytohormone receptors have provided critical insights into the molecular mechanisms of phytohormone perception and signal transduction. Here, we review the structural bases of phytohormone recognition and receptor activation. As a common feature, phytohormones regulate the interaction between the receptors and their respective target proteins (also called co-receptors) by two types of regulatory mechanisms, acting as either “molecular glue” or an “allosteric regulator.” However, individual phytohormone receptors adopt specific structural features that are essential for activation. In addition, recent studies have focused on the molecular diversity of redundant phytohormone receptors.     

A role for lipid rafts in immune cell signaling

Cross-linking of surface receptors in hematopoietic cells results in the enrichment of these receptors in the rafts along with other downstream signaling molecules. A possible explanation how signal is transduced through the plasma membrane has arisen from the concept of raft. From the study of cellular responses in the plasma membrane which enrich members of the Src-family tyrosine kinase, rafts can function as centers of signal transduction by forming patches. Under physiological conditions, these elements synergize to transduce successfully a signal at the plasma membrane. Rafts are suggested to be important in controlling appropriate protein interactions in hematopoietic cells, and aggregation of rafts following receptor ligation may be a general mechanism for promoting immune cell signaling.     

Collagen-platelet interaction: platelet non-integrin receptors

Platelet-collagen interaction is a complex event that involves ligand-receptor interaction. There are many adhesive non-integrin receptors for platelets to interact with various types of collagens. These non-integrin receptors also serve as signal transducers both from the outside of platelets to the inside and possibly vice versa. The present review covers basic aspects of non-integrin receptor function and various signal transduction pathways.     

From binding proteins to hormone receptors?

Phytohormones exert in responsive plant cells specific biochemical and physiological effects. It is a widely held view that phytohormones are first recognized by specific receptors which initiate the transduction of the hormonal signal. While hormone receptors are well studied in many eukaryotes ranging from yeast to man, we are lacking a detailed understanding of phytohormone receptors. Phytohormone binding proteins have been suspected to provide candidates for such receptors. In this review recent progress towards molecular analysis of such proteins and their genes will be summarized.     

The role of the CGRP-receptor component protein (RCP) in adrenomedullin receptor signal transduction.

G protein-coupled receptors are usually thought to act as monomer receptors that bind ligand and then interact with G proteins to initiate signal transduction. In this study we report an intracellular peripheral membrane protein named the calcitonin gene-related peptide (CGRP)-receptor component protein (RCP) required for signal transduction at the G protein-coupled receptor for adrenomedullin. Cell lines were made that expressed an antisense construct of the RCP cDNA, and in these cells diminished RCP expression correlated with loss of adrenomedullin signal transduction. In contrast, loss of RCP did not diminish receptor density or affinity, therefore RCP does not appear to act as a chaperone protein. Instead, RCP represents a novel class of protein required to couple the adrenomedullin receptor to the cellular signal transduction pathway. A candidate adrenomedullin receptor named the calcitonin receptor-like receptor (CRLR) has been described, which forms high affinity adrenomedullin receptors when co-expressed with the accessory protein receptor-activity modifying protein 2 (RAMP2). RCP co-immunoprecipitated with CRLR and RAMP2, indicating that a functional adrenomedullin receptor is composed of at least three proteins: the ligand binding protein (CRLR), an accessory protein (RAMP2), and a coupling protein for signal transduction (RCP).     

The mobile receptor hypothesis revisited: a mechanistic role for hormone receptor lateral mobility in signal transduction.

Recent application of the technique of fluorescence photobleaching recovery to direct measurement of the lateral mobility of plasma membrane-localized hormone receptors has shed new light on the role of receptor lateral mobility in signal transduction. Receptors for insulin and EGF have been known for some time to be largely immobile at physiological temperatures. This presumably relates to their signal transduction mechanism, which appears to require intermolecular autophosphorylation (receptor aggregation) for activation. In contrast, G-protein coupled receptors must interact with other membrane components to bring about signal transduction, and it is interesting in this regard that the adenylate cyclase (AC) activating vasopressin V2-receptor is highly laterally mobile at 37 degrees C. It has recently been possible to reversibly modulate the V2-receptor mobile fraction (f) to largely varying extents, and to demonstrate thereby a direct effect on the maximal rate of in vivo cAMP production at 37 degrees C in response to vasopressin. A direct correlation between f and maximal cAMP production indicates that f may be a key parameter in hormone signal transduction in vivo, especially at sub-KD (physiological) hormone concentrations, with mobile receptors being required to effect G-protein activation.     

The hepatic adrenergic receptors

Summary The presence of both alpha- and beta-adrenergic receptors in liver designated the hepatic plasma membrane as a useful tool for the elucidation of the mechanisms by which the hormonal signal is transfered through the membrane via a coupling system to an amplifying entity. This process is well documented for the beta-adrenergic receptor which is linked to adenylate cyclase, whereby it modulates the cyclic AMP level. Much less is known about the alpha-adrenergic receptor.Recently, two factors have contributed to a renewed interest in alpha- and beta-adrenergic receptors in liver: i) The fact that activation of glycogenolysis in isolated liver parenchymall cells by epinephrine may be mediated by either alpha- or beta-adrenergic receptors, depending on the species or on the state of nutrition, and not only by beta-adrenergic receptors as previously thought. ii) The existence of specific adrenergic agonists and antagonists radiolabeled to a high specific activity which has permitted the characterization of adrenergic receptors in terms of nature, number, affinity and regulation.The present review will be devoted to the recent progress made in the physiological, pharmacological and biochemical characterization of alpha- and beta-adrenergic receptors in the liver.     

Endocytic regulation of cytokine receptor signaling

Signaling of plasma membrane receptors can be regulated by endocytosis at different levels, including receptor internalization, endocytic sorting towards degradation or recycling, and using endosomes as mobile signaling platforms. Increasing number of reports underscore the importance of endocytic mechanisms for signaling of cytokine receptors. In this short review we present both consistent and conflicting data regarding endocytosis and its role in signaling of receptors from the tumor necrosis factor receptor superfamily (TNFRSF) and those for interleukins (ILRs) and interferons (IFNRs). These receptors can be internalized through various endocytic routes and most of them are able to activate downstream pathways from endosomal compartments. Moreover, some of the cytokine receptors clearly require endocytosis for proper signal transduction. Still, the data describing internalization mechanisms and fate of cytokine receptors are often fragmentary and barely address the relation between their endocytosis and signaling. In the light of growing knowledge regarding different mechanisms of endocytosis, extending it to the regulation of cytokine receptor signaling may improve our understanding of the complex and pleiotropic functions of these molecules.     

A method for determining the classification of a protein in a given family at a low level of similarity]

Basing on the analysis of the primary structure of proteins from a family of signal receptor proteins, the existence of short extremely conservative family-specific chains was postulated. These chains may serve as a marker in determination of the relationship of a protein to the given family. On the basis of the performed analysis, it is suggested that mass-oncogene belongs to the family of signal receptors, whereas pheromonal receptor of the yeasts STE-2--presumably does not.     

Protein Clusters in Phosphotyrosine Signal Transduction

Signal transduction systems based on tyrosine phosphorylation are central to cell–cell communication in multicellular organisms. Typically, in such a system, the signal is initiated by activating tyrosine kinases associated with transmembrane receptors, which induces tyrosine phosphorylation of the receptor and/or associated proteins. The phosphorylated tyrosines then serve as docking sites for the binding of various downstream effector proteins. It has long been observed that the cooperative association of the receptors and effectors produces higher-order protein assemblies (clusters) following signal activation in virtually all phosphotyrosine signal transduction systems. However, mechanistic studies on how such clustering processes affect signal transduction outcomes have only emerged recently. Here we review current progress in decoding the biophysical consequences of clustering on the behavior of the system, and how clustering affects how these receptors process information.