Receptors & Clinical Investigation (E-Journal - Smart Science & Technology)
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Nicotinic and non-nicotinic receptor-mediated mechanisms responsible for anti-atrophy effects in muscle
Get PDFRecently, cholinergic modulation of immune cells has drawn particular interests from researchers in clinical fields, which may lead to a breakthrough that produces a novel therapeutic modality. Other than the immunological aspects, cholinergic modulation may also provide clues for accelerating angiogenesis and preventing any associated muscle atrophy. In this Research highlight, we discuss our recent findings in the context of research advancements, focusing on nicotinic and non-nicotinic receptor-mediated anti-muscular atrophy effects
The Androgen Receptor Is a Key Component of Myometrium Phenotype Programming During Pregnancy
Get PDFThe economic burden associated with preterm birth is significant to our society. While research efforts on preterm birth over past decades had been directed toward understanding the late stage of parturition, recent discoveries have indicated that the timing of labour is delicately programmed as early as the initiation of pregnancy. We have proposed that there exists a myometrium phenotype programming during pregnancy consisting three characteristic stages referred to as the early proliferative, the midterm hypertrophic and the late contractile stages. This remarkable plasticity of myometrium allows it not only provides containment for fetus to be fully developed within the womb during pregnancy, but also performs coordinate contractions at the onset of labor to expel the fetus into extrauterine environment. Our two recent studies further demonstrate that the androgen receptor is a key component of myometrium phenotype programming. Here we summarize our endeavor in characterizing the androgen receptor signaling in myometrial smooth muscle cells
Chemokine receptors on the defensive – the surprising role of CXCR4 in brown adipose tissue
Get PDFObesity, which is triggered by over-nutrition and supported by the excessive expansion of adipose tissue due to hyperplasia and hypertrophy, has been linked to an increased incidence of type 2 diabetes, hypertension, cardiovascular disease and cancer. Since obesity-induced co-morbidities impose a significant financial burden on healthcare systems in Western societies, clear understanding of molecules and mechanisms supporting physiologic and pathologic activities of adipose tissue is mandatory. Abundant evidence shows that development of obesity is facilitated by a low-grade inflammation fueled by infiltration of pro-inflammatory leukocytes into white adipose tissue pads, which is in part mediated by chemokines and chemokine receptors. However, not all members of the chemokine system facilitate development of obesity. In this publication we highlight a surprising role of CXCR4 in fat cells where this chemokine receptor promotes energy expenditure and prevents excessive inflammatory leukocyte recruitment into adipose tissue, and by so doing, limits obesity
The multiple signaling modalities of adhesion G protein-coupled receptor GPR126 in development
Get PDFThe G protein-coupled receptor (GPCR) superfamily is the largest known receptor family in the human genome. Although the family of adhesion GPCRs comprises the second largest sub-family, their function is poorly understood. Here, we review the current knowledge about the adhesion GPCR family member GPR126. GPR126 possesses a signal peptide, a 7TM domain homologous to secretin-like GPCRs, a GPS motif and an extended N-terminus containing a CUB (Complement, Uegf, Bmp1) domain, a PTX (Pentraxin) domain, a hormone binding domain and 27 putative N-glycosylation sites. Knockdown and knockout experiments in zebrafish and mice have demonstrated that Gpr126 plays an essential role in neural, cardiac and ear development. In addition, genome-wide association studies have implicated variations at the GPR126 locus in obstructive pulmonary dysfunction, in scoliosis and as a determinant of trunk length and body height. Gpr126 appears to exert its function depending on the organ system via G-protein- and/or N-terminus-dependent signaling. Here, we review the current knowledge about Gpr126, which, due to the variety of its functions and its multiple signaling modalities, provides a model adhesion GPCR to understand general functional concepts utilized by adhesion GPCRs
Dual, Postsynaptic 5-HT2B Antagonist and 5-HT1A Agonist Approach to the Treatment of METH/MDMA Addiction and Related Behavioral Disorders
Get PDFThe synthesis, in vitro, and preliminary in vivo pharmacology of DDD-024, a novel, pentacyclic compound, is described. It exhibits high affinity to the 5-HT1A and good affinity to the 5-HT2B receptors and is an agonist of the former and antagonist of the latter receptor, a profile which meets with the requirements delineated in our hypothesis proposed in Part 1 (see previous paper). Further, in vivo, it was quite active in METH-seeking behavior test in rats, MDMA-induced hyperlocomotion test in mice, and Porsolt’s forced swim test in rats for antidepressant activity thereby providing definite proof of concept for our hypothesis
vGPCR, The Great Escape
Get PDFKaposi Sarcoma (KS), a connective tissue cancer that may affect the skin and internal organs, is associated with human herpes virus 8 (HHV-8) infection. Among the oncogenes encoded by HHV8, the viral G protein coupled receptor (vGPCR ORF74) was found instrumental for sarcomagenesis initiation and progression. Indeed, vGPCR displays permanent activation, and is sufficient to induce tumor development in mice. However, the molecular mechanisms controlling vGPCR expression and activation remain poorly understood. Here, we present recent data from our group highlighting the presence of an endocytosis motif (Y326GLF) in the vGPCR C-terminal domain that orchestrates the receptor cellular localization, as well as its signaling and paracrine actions. We further show that this YGLF motif controls TLR4 surface expression, and may thus assure immune surveillance. In conclusion, this work shed light on the importance of vGPCR cellular localization and trafficking for its pathogenicity
Structural variation of G protein-coupled receptor in birds
Get PDFG protein-coupled receptors (GPCRs) are key regulators of various vital biological processes. Regardless of their physiological significance, GPCRs generally harbor a certain number of amino acid substitutions, as well as insertions/deletions, particularly in the loop and tail regions, even at the species level. We previously revealed that the C-terminal domain of avian GPCRs shows length variations at the intra-species level. The presence or absence of deletion in helix 8 of the arginine vasotocin receptor affected the pattern of putative palmitoylation sites in the zebra finch. Moreover, Turdus thrushes harbored 18-amino acid tandem duplications at the distal part of the C-terminal tails of the mesotocin receptor. These findings illustrated that avian neuropeptide receptors accommodate structural changes at the C-terminal tails as a source of genetic variation that may lead to phenotypic differences in natural populations as a consequence of natural selection
Functional analyses and affinity-alteration of receptors and enzymes based on membrane recruitment of yeast guanine nucleotide-binding protein gamma subunit
Get PDFTo investigate fundamental processes conserved in all eukaryotic cells, the budding yeast Saccharomyces cerevisiae has being widely used as a model organism. In particular, the yeast two-hybrid system is a powerful technique for analyzing protein–protein interactions and protein function in living cells. Here, we describe several approaches for investigating and regulating the activity of target proteins using the yeast guanine nucleotide-binding protein (G-protein) signaling machinery as the readout. These approaches are rapid and easy-to-use tools that support the design of regulatory factors against receptors, enzymes, and other proteins that have been identified as potential drug target molecules. 
Transcriptional and non-transcriptional roles of LXRs in cancer cells
Get PDFLiver X Receptors (LXRs) have been proposed to have some anticancer properties. LXRs affect cancer cell proliferation and cell death through mechanisms that seems mostly to rely on its transcriptional activities. We recently identified a new non-genomic role of LXR? in colon cancer cells. Under LXR agonist treatment, LXR? induces an atypical cell death called pyroptosis in vitro and in vivo. Together with other reports, we raise the importance of targeting LXRs in cancer treatment
ArfGAPs: key regulators for receptor sorting
Get PDFMammalian cells have many membranous organelles that require proper composition of proteins and lipids. Cargo sorting is a process required for transporting specific proteins and lipids to appropriate organelles, and if this process is disrupted, organelle function as well as cell function is disrupted. ArfGAP family proteins have been found to be critical for receptor sorting. In this review, we summarize our recent knowledge about the mechanism of cargo sorting that require function of ArfGAPs in promoting the formation of transport vesicles, and discuss the involvement of specific ArfGAPs for the sorting of a variety of receptors, such as MPR, EGFR, TfR, Glut4, TRAIL-R1/DR4, M5-muscarinic receptor, c-KIT, rhodopsin and ?1-integrin. Given the importance of many of these receptors to human disease, the studies of ArfGAPs may provide novel therapeutic strategies in addition to providing mechanistic insight of receptor sorting