Receptors & Clinical Investigation (E-Journal - Smart Science & Technology)
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Using the newly developed nanoluciferase as an ultrasensitive bioluminescent probe for ligand-receptor interaction studies
Get PDFNanoluciferase (NanoLuc) is a newly developed small monomeric luciferase reporter with the brightest bioluminescence reported to date. Recently, we have used NanoLuc as a novel ultrasensitive bioluminescent probe for ligand-receptor interaction studies. In the present highlight, I discuss its general application in ligand-receptor interactions and other binding studies. This novel ultrasensitive bioluminescent probe will facilitate a wide range of biological studies as its new applications are continuously developed
Epigenetic regulation of corticotropin-releasing hormone receptor 1: implication for anxiety-related disorders
Get PDFRecent literature corroborates that both, genes and environment, are crucial determinants contributing to psychiatric disorders. The selectively bred mouse models of enhanced fear and anxiety-related behavior provide a unique opportunity to study the interaction of a rigid genetic predisposition with environmental factors and are used to identify targets contributing to pathological anxiety. Here, we studied gene × environment (G×E) interactions using a mouse model of high (HAB) vs. low (LAB) anxiety-related behavior. By applying enriched environment (EE) and chronic mild stress (CMS), we succeeded in shifting the phenotypes of HAB and LAB mice towards “normal” anxiety. In this bidirectional shift, Crhr1 was identified to be a key player. Increased methylation of CpG1 within the Crhr1 promoter region was shown to be critically involved in regulating the binding affinity of the transcription factor Ying-Yang 1 (YY1). The interplay between YY1 expression and DNA methylation might be the mechanism underlying the differences in Crhr1 expression after EE and CMS. Other epigenetic mechanisms contributing to Crhr1 expression are discussed here
Lysophosphatidic acid LPA1-3 receptors: signaling, regulation and in silico analysis of their putative phosphorylation sites
Get PDFLysophosphatidic acid (LPA) is a bioactive lipid with a plethora of roles in the normal function of our organism as well as in the pathogenesis of many diseases. The actions of LPA are mainly mediated through a family of G protein-coupled receptors, which currently is composed of six members; other receptors might participate in LPA actions including a nuclear receptor. In this work, we mainly focus on three of these receptors, i. e., LPA1-3; those that were initially discovered which, have been more extensively studied and that are phylogenetically related among themselves, as well as with receptors for other bioactive phospholipids, such as those for spingosine 1-phosphate. The characteristics of these receptors, their patterns of tissue expression, and some of the actions in which they are involved are presented. Regulation of receptor function, including desensitization, internalization and phosphorylation has only been studied for the LPA1 subtype. However, in silico analysis of potential phosphorylation sites indicate that all of these three receptors are putatively regulated by agonist activation and heterologous stimuli. We think LPA1-3 receptor regulation constitutes a niche of investigation that is potentially of great importance considering the physiological and pathophysiological actions in which they are involved. 
Hallucinogens induce a specific barcode of phosphorylation on the serotonin2A receptor that underlies a weaker receptor desensitization and internalization
Get PDFThe serotonin (5-Hydroxytryptamine, 5-HT)2A receptor represents one of the most striking examples where functional selectivity (or ligand-biased signaling) is transduced in distinct behaviours. This receptor is the primary target of psychedelic hallucinogens such as lysergic acid diethylamine, mescaline and psilocybin, which reproduce some of the core symptoms of schizophrenia and are often used to probe the disease. Why only some 5-HT2A receptor agonists exhibit hallucinogenic activity, whereas structurally related agonists with comparable affinity and agonist activity (e.g. lisuride and ergotamine) lack such a psychoactive activity remains an incompletely resolved paradox. In a recent paper published in Molecular and Cellular Proteomics (doi: 10.1074/mcp.M113.036558) we demonstrated a biased phosphorylation of the 5-HT2A receptor in response to hallucinogenic versus non-hallucinogenic agonists that leads to a weaker receptor desensitization and internalization by hallucinogens
The functions and signaling pathways induced by the interactions of APP–related molecules with p75NTR
Get PDFp75 neurotrophin receptor (p75NTR) regulates diverse functions, including survival, differentiation, growth, and apoptosis of neurons, through its association with a number of molecules. Accumulating evidence shows that ?-amyloid precursor protein (APP)–related molecules, which also regulate multiple neuronal functions, interact with p75NTR. APP is cleaved by secretases to generate several proteins including soluble ?-amyloid precursor protein alpha (sAPP?), sAPP?, and amyloid ? (A?). Binding of A? to p75NTR induces neuronal death. In contrast, sAPP? directly interacts with p75NTR to enhance neurite outgrowth through the activation of protein kinase A (PKA). This review focuses on the molecular mechanisms and functions occurring as a consequence of interactions of p75NTR with APP–related molecules
Renin blockade: a double-edged sword?
Get PDFAliskiren, a direct renin inhibitor, blocks the first step of the renin–angiotensin–aldosterone system (RAAS), thereby reducing plasma renin activity and the circulating levels of angiotensin I, angiotensin II, and aldosterone. Extensive RAAS blockade can be achieved through the administration of aliskiren; however, renin blockade is a double-edged sword because the renin/prorenin receptor-associated pathway is also reportedly modulated by direct renin inhibitor. This research highlight discusses the findings of a recent clinical study of aliskiren and explores the complex interactions of key molecules in the RAAS pathway in response to aliskiren administration
5-hydroxytryptamine type-3A receptor in the process of fear extinction
Get PDFThe 5-hydroxytryptamine type-3 (5-HT3) receptor is the only ionotropic receptor in the family of 5-HT receptors. The 5-HT3 receptor is expressed in limbic regions, such as hippocampus, amygdala and cortex. However, it is not known whether it has a role in fear memory processes. We performed behavioral analyses of 5-HT3A receptor knockout mice in fear conditioning paradigms, and revealed that the 5-HT3A receptor is not required for the acquisition or retention of fear memory but is essential for the extinction of learned fear. Furthermore, we found that the 5-HT3A receptor contributes to the context-specificity of extinction processes. Our results suggest that the 5-HT3A receptor could be a key molecule for regulation of fear extinction, and potentially important therapeutic target for disorders of regulation in fear systems, such as post-traumatic stress-disorder (PTSD)
Identification of a series of 3-(benzo[d]oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amines, as a new class of G-protein-coupled receptor kinase 2 and 5 inhibitor
Get PDFThe arising critical implications of G-protein-coupled receptor kinase 2 and 5 (GRK2 and 5) in heart failure have been attracting attention and inhibitors of GRK2 and 5 were considered as a novel therapeutic strategy to prevent and treat heart failure disease. Despite this large therapeutic potential, to date few GRK2 inhibitors have been identified and GRK5 inhibitors in public have been unknown. In our efforts to discover a novel scaffold with potent GRK2 and GRK5 inhibitory activities, we found that a series of 3-(benzo[d]oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amines have been identified as a new class of GRK2 and 5 kinase inhibitor. Structural modification of parent benzoxazole scaffolds by introducing substituents on phenyl displayed potent inhibitory activities toward GRK2 and 5. This research highlight discusses the processing and findings of the recent study
Relationship between inflammation and cancer progression: Recent advances in interleukin-6 signaling and its blockage in cancer therapy
No full textInterleukin-6 (IL-6) is a well-known pro-inflammatory cytokine with pleiotropic bioactivity and is mainly produced by inflammatory cells. Several diseases are influenced by IL-6; thus, the anti-IL-6 receptor antibody has been used clinically e.g., in the treatment of rheumatoid disease and Castleman disease. Signal transduction through gp130 occurs primarily via the JAK/STAT pathway and secondarily via the PI3K and MAPK pathways. Activation of STAT3 is an important step for the expression of various genes associated with carcinogenesis and cancer progression. Experiments using STAT3 inhibitor and IL-6 shRNA have shown that the activation of STAT3 is necessary for cancer cell proliferation and survival. Several studies have also demonstrated that IL-6 exhibits characteristics associated with both inflammatory cytokines and proangiogenic factors. These studies have demonstrated that IL-6 contributes to angiogenesis as a potent inducer of VEGF, which is one of the most important angiogenic factors. Recently, it has also been reported that cancer–stromal interactions are necessary steps during cancer progression, such as during angiogenesis. These mechanisms of IL-6, which affect cancer cells directly and through cancer–stromal interactions are essential for cancer progression and are of various types. Therefore, increasing attention is being paid to IL-6 signaling as a novel cancer therapeutic approach. This review summarizes the role of IL-6 signaling from the viewpoint of cancer progression and the potency of the anti-IL-6 signaling antibody during cancer therapy
Role of Protease-Activated Receptors 2 (PAR2) in Ocular Infections and Inflammation
Get PDFProtease-activated receptors (PARs) belong to a unique family of G protein-coupled receptors (GPCRs) that are cleaved at an activation site within the N-terminal exodomain by a variety of proteinases, essentially of the serine (Ser) proteinase family. After cleavage, the new N-terminal sequence functions as a tethered ligand, which binds intramolecularly to activate the receptor and initiate signaling. Cell signals induced through the activation of PARs appear to play a significant role in innate and adoptive immune responses of the cornea, which is constantly exposed to proteinases under physiological or pathophysiological conditions. Activation of PARs interferes with all aspects of the corneal physiology such as barrier function, transports, innate and adoptive immune responses, and corneal nerves functions. It is not known whether the proteinase released from the microorganism can activate PARs and triggers the inflammatory responses. The role of PAR2 expressed by the corneal epithelial cells and activation by serine protease released from microorganism is discussed here. Recent evidences suggest that activation of PAR2, by the serine proteinases, play an important role in innate and inflammatory responses of the corneal infection