Genome-wide prediction of G protein-coupled receptors in Verticillium spp

G protein-coupled receptors (GPCRs) are critical factors in regulating morphogenesis, mating, infection and virulence in fungi. In this study, various computational strategies were applied to identify GPCR-like proteins from the genomes of both Verticillium dahliae and Verticillium albo-atrum. The putative GPCRs were distributed over 13 classes, and significantly, three of those represented novel classes of GPCR-like proteins in fungi. The three novel GPCRs had high levels of identity to their counterparts in higher eukaryotes, including Homo sapiens. The numbers of GPCR-like proteins in the two Verticillium spp. were similar to those seen in other filamentous fungi, such as Magnaporthe grisea, Neurospora crassa and Fusarium graminearum. Additionally, the carbon/amino acid receptors were divided into three different subclasses, indicating that differences among the GPCRs existed not only among different classes but also within classes. In conclusion, the identification and classification of GPCRs and their homology to some well-studied fungi will be an important starting point for future research in Verticillium spp.     

G protein-coupled receptors.

The diversity of the G protein-coupled receptor superfamily is now being realised with the molecular cloning of DNA encoding many new receptors and receptor subfamilies. The existing pharmacological definitions of receptor subtypes have been extended dramatically with identification of additional subtypes at the molecular level. Functional analysis of cloned receptors by expression in heterologous cell types has demonstrated that individual receptor subtypes can couple to a variety of different effector systems.     

Lysophospholipid G protein-coupled receptors

The many biological responses documented for lysophospholipids that include lysophosphatidic acid and sphingosine 1-phosphate can be mechanistically attributed to signaling through specific G protein-coupled receptors. At least nine receptors have now been identified, and the total number is likely to be larger. In this brief review, we note cogent features of lysophospholipid receptors, including the current nomenclature, signaling properties, development of agonists and antagonists, and physiological functions.     

Olfactory receptors: G protein-coupled receptors and beyond

Sensing the chemical environment is critical for all organisms. Diverse animals from insects to mammals utilize highly organized olfactory system to detect, encode, and process chemostimuli that may carry important information critical for health, survival, social interactions and reproduction. Therefore, for animals to properly interpret and react to their environment it is imperative that the olfactory system recognizes chemical stimuli with appropriate selectivity and sensitivity. Because olfactory receptor proteins play such an essential role in the specific recognition of diverse stimuli, understanding how they interact with and transduce their cognate ligands is a high priority. In the nearly two decades since the discovery that the mammalian odorant receptor gene family constitutes the largest group of G protein-coupled receptor (GPCR) genes, much attention has been focused on the roles of GPCRs in vertebrate and invertebrate olfaction. However, is has become clear that the 'family' of olfactory receptors is highly diverse, with roles for enzymes and ligand-gated ion channels as well as GPCRs in the primary detection of olfactory stimuli.     

Downregulation of G protein-coupled receptors

Major advances have been made in understanding mechanisms mediating downregulation of G protein-coupled receptors. Recent studies emphasize the role of multiple proteolytic mechanisms in downregulation. A specific mechanism of downregulation, mediated by endocytosis of receptors via clathrin-coated pits followed by sorting to lysosomes, has been examined in detail. Specific protein interactions that control the specificity of G-protein-coupled receptor trafficking in this pathway are beginning to be elucidated.     

Mechanisms of G protein-coupled receptors regulation

Within the last two decades of studies in the ever-expanding field of GPCR signaling, challenging insights were adopted. Growing evidence now asists the shift from classical linear model of signaling towards a considerably complex network of signaling pathways with many shared proteins and cross-talks. Considering the extensive and intriguing network of pathways activated by these receptors, it is apparent that multi-level system of regulation must exist to rigorously modulate the amplitude, duration and spatial aspects of the GPCR signaling. This review summarizes the principal mechanisms of GPCR regulation and gives the overview of recent advances in this field of research.     

Structural biology of G protein-coupled receptors

More than 60% of the current drugs are based on G protein-coupled receptors. Paradoxically, high-resolution structures are not available to facilitate rational drug design. Difficulties in expression, purification, and crystallization of these transmembrane receptors are the reasons for the low success rate. Recent individual and network-based technology development has significantly improved our knowledge of structural biology and might soon bring a major breakthrough in this area.     

Splice variants of G protein-coupled receptors

G protein-coupled receptors (GPCRs) are encoded by a vast gene superfamily, reflecting the large number of ligands that must be specifically recognized at any given cell surface. The discovery that the variety of GPCRs is further expanded through the generation of splice variants was therefore somewhat surprising. Studies of the functional consequences of alternative splicing have focused on ligand binding, signaling, constitutive activity, and downregulation. However, GPCRs also appear to interact directly with many other intracellular proteins in addition to G proteins. Intriguingly, the domains involved in these interactions are the predominant sites of variation arising through splicing.     

Desensitization of herpesvirus-encoded G protein-coupled receptors

Members of the herpesvirus family, including human cytomegalovirus (HCMV) and Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8), encode G protein-coupled receptor (GPCR) homologs, which strongly activate classical G protein signal transduction networks within the cell. In animal models of herpesvirus infection, the viral GPCRs appear to play physiologically important roles by enabling viral replication within tropic tissues and by promoting reactivation from latency. While a number of studies have defined intracellular signaling pathways activated by herpesviral GPCRs, it remains unclear if their physiological function is subjected to the process of desensitization as observed for cellular GPCRs. G protein-coupled receptor kinases (GRK) and arrestin proteins have been recently implicated in regulating viral GPCR signaling; however, the role that these desensitization proteins play in viral GPCR function in vivo remains unknown. Here, we review what is currently known regarding viral GPCR desensitization and discuss potential biological ramifications of viral GPCR regulation by the host cell desensitization machinery.     

Agonist-bound structures of G protein-coupled receptors

G protein-coupled receptors (GPCRs) play a major role in intercellular communication by binding small diffusible ligands (agonists) at the extracellular surface. Agonist-binding induces a conformational change in the receptor, which results in the binding and activation of heterotrimeric G proteins within the cell. Ten agonist-bound structures of non-rhodopsin GPCRs published last year defined for the first time the molecular details of receptor activated states and how inverse agonists, partial agonists and full agonists bind to produce different effects on the receptor. In addition, the structure of the β(2)-adrenoceptor coupled to a heterotrimeric G protein showed how the opening of a cleft in the cytoplasmic face of the receptor as a consequence of agonist binding results in G protein coupling and activation of the G protein.     

G蛋白偶联受体的结构生物学研究

G蛋白偶联受体(G protein-coupled receptor,GPCR)在细胞信号转导过程中发挥关键的生理学功能,是极其重要的药物靶标,其三维结构信息对功能研究以及新药研发具有十分重要的意义。近年来,新技术的发展和应用使GPCR的结构生物学研究发生了跨越式的发展,本文简要回顾这些新的技术和方法以及已解析的GPCR三维结构,并以CCR5和P2Y12R两种受体的结构为例来具体阐明现阶段GPCR结构生物学研究的内容和意义。     

G protein-coupled receptors in energy homeostasis

G-protein coupled receptors (GPCRs) compromise the largest membrane protein superfamily which play vital roles in physiological and pathophysiological processes including energy homeostasis. Moreover, they also represent the up-to-date most successful drug target. The gut hormone GPCRs, such as glucagon receptor and GLP-1 receptor, have been intensively studied for their roles in metabolism and respective drugs have developed for the treatment of metabolic diseases such as type 2 diabetes (T2D). Along with the advances of biomedical research, more GPCRs have been found to play important roles in the regulation of energy homeostasis from nutrient sensing, appetite control to glucose and fatty acid metabolism with various mechanisms. The investigation of their biological functions will not only improve our understanding of how our body keeps the balance of energy intake and expenditure, but also highlight the possible drug targets for the treatment of metabolic diseases. The present review summarizes GPCRs involved in the energy control with special emphasis on their pathophysiological roles in metabolic diseases and hopefully triggers more intensive and systematic investigations in the field so that a comprehensive network control of energy homeostasis will be revealed, and better drugs will be developed in the foreseeable future.     

G蛋白偶联受体在血管发育中的作用

血管发育包括血管发生和血管生成两个阶段。近年研究表明, G蛋白偶联受体广泛参与调控成血管细胞的分化、迁移和接合, 尖端细胞和柄细胞命运决定, 内皮细胞的增殖、迁移和管腔形成等多个过程。文章以血管发育中的这些关键事件为主线, 总结了G蛋白偶联受体家族成员特别是视紫红质类和卷曲类受体在调节血管发育方面的最新研究进展。文章着重介绍了斑马鱼作为模式生物在血管发育生物学研究中的独特优势, 并展望了利用斑马鱼深入开展G蛋白偶联受体相关研究的广阔前景。     

Biased agonism at G protein-coupled receptors

G protein-coupled receptors (GPCRs) represent the largest family of approved therapeutic targets. Ligands stimulating these receptors specifically activate multiple signalling pathways that induce not only the desired therapeutic response, but sometimes untolerated side effects that limit their clinical use. The diversity in signalling induced by each ligand could be considered a viable path for improving this situation. Biased agonism, which offers the promise of identifying pathway-selective drugs has been proposed as a means to exploit this opportunity. However, identifying biased agonists is not an easy process and quantifying ligand bias for a given signalling pathway requires careful consideration and control of several confounding factors. To date, the molecular mechanisms of biased signalling remain unclear and known theories that constitute our understanding of the mechanisms underlying therapeutic and side effects are still being challenged, making the strategy of selecting promising potential drugs more difficult. This special issue summarizes the latest advances in the discovery and optimization of biased ligands for different GPCRs. It also focuses on identifying novel insights into the field of biased agonism, while at the same time, highlighting the conceptual and experimental limitations of that concept for drug discovery. This aims to broaden our understanding of the signalling induced by the various identified biased agonists and provide perspectives that could straighten our path towards the development of more effective and tolerable therapeutics.     

G protein-coupled receptors in cardiac biology: old and new receptors

G protein-coupled receptors (GPCRs) are seven-transmembrane-spanning proteins that mediate cellular and physiological responses. They are critical for cardiovascular function and are targeted for the treatment of hypertension and heart failure. Nevertheless, current therapies only target a small fraction of the cardiac GPCR repertoire, indicating that there are many opportunities to investigate unappreciated aspects of heart biology. Here, we offer an update on the contemporary view of GPCRs and the complexities of their signalling, and review the roles of the ‘classical’ GPCRs in cardiovascular physiology and disease. We then provide insights into other GPCRs that have been less extensively studied in the heart, including orphan, odorant and taste receptors. We contend that these novel cardiac GPCRs contribute to heart function in health and disease and thereby offer exciting opportunities to therapeutically modulate heart function.     

Homo- and hetero-oligomerization of G protein-coupled receptors

G protein-coupled receptors (GPCRs) form homo-oligomeric and hetero-oligomeric complexes. This understanding has prompted a re-evaluation of many aspects of GPCR biology, however the concept of receptor complexes has not been fully integrated into the current thinking about GPCR structure and function. Nevertheless, receptor oligomerization is a pivotal aspect of the structure and function of GPCRs that has been shown to have implications for receptor trafficking, signaling, and pharmacology and more intricate models for understanding the physiological roles of these receptors are emerging. Here, we summarize some of the advances made in understanding the structural basis and the functional roles of homo- and hetero- oligomerization in this important group of receptors. Although this discussion focuses primarily on the dopamine receptors, particularly the D2 dopamine receptor, and the opioid and serotonin receptors, we discuss the principles governing the oligomerization of all rhodopsin-like GPCRs and potentially of the entire superfamily of these receptors.     

G protein-coupled odorant receptors: From sequence to structure

Odorant receptors (ORs) are the largest subfamily within class A G protein-coupled receptors (GPCRs). No experimental structural data of any OR is available to date and atomic-level insights are likely to be obtained by means of molecular modeling. In this article, we critically align sequences of ORs with those GPCRs for which a structure is available. Here, an alignment consistent with available site-directed mutagenesis data on various ORs is proposed. Using this alignment, the choice of the template is deemed rather minor for identifying residues that constitute the wall of the binding cavity or those involved in G protein recognition.