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Cancers Nov 2020Dopamine is a biologically active compound belonging to catecholamines. It plays its roles in the human body, acting both as a circulating hormone and neurotransmitter.... (Review)
Review
Dopamine is a biologically active compound belonging to catecholamines. It plays its roles in the human body, acting both as a circulating hormone and neurotransmitter. It acts through G-protein-coupled receptors divided into two subgroups: D1-like receptors (D1R and D5R) and D2-like receptors (D2R, D3R, D4R). Physiologically, dopamine receptors are involved in central nervous system functions: motivation or cognition, and peripheral actions such as blood pressure and immune response modulation. Increasing evidence indicates that the dopamine D1 receptor may play a significant role in developing different human neoplasms. This receptor's value was presented in the context of regulating various signaling pathways important in tumor development, including neoplastic cell proliferation, apoptosis, autophagy, migration, invasiveness, or the enrichment of cancer stem cells population. Recent studies proved that its activation by selective or non-selective agonists is associated with significant tumor growth suppression, metastases prevention, and tumor microvasculature maturation. It may also exert a synergistic anti-cancer effect when combined with tyrosine kinase inhibitors or temozolomide. This review provides a comprehensive insight into the heterogeneity of dopamine D1 receptor molecular roles and signaling pathways in human neoplasm development and discusses possible perspectives of its therapeutic targeting as an adjunct anti-cancer strategy of treatment. We highlight the priorities for further directions in this research area.
PubMed: 33147760
DOI: 10.3390/cancers12113232 -
Cells Jun 2023The glucocorticoid receptor α (GRα) is a member of the nuclear receptor superfamily and functions as a glucocorticoid (GC)-responsive transcription factor. GR can halt... (Review)
Review
The glucocorticoid receptor α (GRα) is a member of the nuclear receptor superfamily and functions as a glucocorticoid (GC)-responsive transcription factor. GR can halt inflammation and kill off cancer cells, thus explaining the widespread use of glucocorticoids in the clinic. However, side effects and therapy resistance limit GR's therapeutic potential, emphasizing the importance of resolving all of GR's context-specific action mechanisms. Fortunately, the understanding of GR structure, conformation, and stoichiometry in the different GR-controlled biological pathways is now gradually increasing. This information will be crucial to close knowledge gaps on GR function. In this review, we focus on the various domains and mechanisms of action of GR, all from a structural perspective.
Topics: Humans; Glucocorticoids; Receptors, Glucocorticoid; Transcription Factors
PubMed: 37371105
DOI: 10.3390/cells12121636 -
Neuropharmacology Aug 2021Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate the majority of excitatory neurotransmission in the vertebrate CNS. Classified as... (Review)
Review
Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate the majority of excitatory neurotransmission in the vertebrate CNS. Classified as AMPA, kainate, delta and NMDA receptors, iGluRs are central drivers of synaptic plasticity widely considered as a major cellular substrate of learning and memory. Surprisingly however, five out of the eighteen vertebrate iGluR subunits do not bind glutamate but glycine, a neurotransmitter known to mediate inhibitory neurotransmission through its action on pentameric glycine receptors (GlyRs). This is the case of GluN1, GluN3A, GluN3B, GluD1 and GluD2 subunits, all also binding the D amino acid d-serine endogenously present in many brain regions. Glycine and d-serine action and affinities broadly differ between glycinergic iGluR subtypes. On 'conventional' GluN1/GluN2 NMDA receptors, glycine (or d-serine) acts in concert with glutamate as a mandatory co-agonist to set the level of receptor activity. It also regulates the receptor's trafficking and expression independently of glutamate. On 'unconventional' GluN1/GluN3 NMDARs, glycine acts as the sole agonist directly triggering opening of excitatory glycinergic channels recently shown to be physiologically relevant. On GluD receptors, d-serine on its own mediates non-ionotropic signaling involved in excitatory and inhibitory synaptogenesis, further reinforcing the concept of glutamate-insensitive iGluRs. Here we present an overview of our current knowledge on glycine and d-serine agonism in iGluRs emphasizing aspects related to molecular mechanisms, cellular function and pharmacological profile. The growing appreciation of the critical influence of glycine and d-serine on iGluR biology reshapes our understanding of iGluR signaling diversity and complexity, with important implications in neuropharmacology.
Topics: Animals; Binding Sites; Glutamic Acid; Glycine; Humans; Ligands; Mice; Receptors, Ionotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Serine; Synaptic Transmission; Xenopus laevis
PubMed: 34058193
DOI: 10.1016/j.neuropharm.2021.108631 -
PloS One 2021Eph receptors are the largest group amongst the receptor tyrosine kinases and are divided into two subgroups, A and B, based on ligand binding specificities and sequence...
Eph receptors are the largest group amongst the receptor tyrosine kinases and are divided into two subgroups, A and B, based on ligand binding specificities and sequence conservation. Through ligand-induced and ligand-independent activities, Ephs play central roles in diverse biological processes, including embryo development, regulation of neuronal signaling, immune responses, vasculogenesis, as well as tumor initiation, progression, and metastasis. The Eph extracellular regions (ECDs) are constituted of multiple domains, and previous structural studies of the A class receptors revealed how they interact with ephrin ligands and simultaneously mediate Eph-Eph clustering necessary for biological activity. Specifically, EphA structures highlighted a model, where clustering of ligand-bound receptors relies on two distinct receptor/receptor interfaces. Interestingly, most unliganded A class receptors also form an additional, third interface, between the ligand binding domain (LBD) and the fibronectin III domain (FN3) of neighboring molecules. Structures of B-class Eph ECDs, on the other hand, have never been reported. To further our understanding of Eph receptor function, we crystallized the EphB6-ECD and determined its three-dimensional structure using X-ray crystallography. EphB6 has important functions in both normal physiology and human malignancies and is especially interesting because this atypical receptor innately lacks kinase activity and our understanding of the mechanism of action is still incomplete. Our structural data reveals the overall EphB6-ECD architecture and shows EphB6-LBD/FN3 interactions similar to those observed for the unliganded A class receptors, suggesting that these unusual interactions are of general importance to the Eph group. We also observe unique structural features, which likely reflect the atypical signaling properties of EphB6, namely the need of co-receptor(s) for this kinase-inactive Eph. These findings provide new valuable information on the structural organization and mechanism of action of the B-class Ephs, and specifically EphB6, which in the future will assist in identifying clinically relevant targets for cancer therapy.
Topics: Cell Line; Crystallography, X-Ray; Ephrins; Fibronectins; Humans; Ligands; Phosphorylation; Protein Binding; Protein Domains; Receptor, EphA1; Receptor, EphB6; Receptors, Eph Family; Signal Transduction
PubMed: 33770085
DOI: 10.1371/journal.pone.0247335 -
Handbook of Experimental Pharmacology 2022Umami, the fifth taste, has been recognized as a legitimate taste modality only recently relative to the other tastes. Dozens of compounds from vastly different chemical...
Umami, the fifth taste, has been recognized as a legitimate taste modality only recently relative to the other tastes. Dozens of compounds from vastly different chemical classes elicit a savory (also called umami) taste. The prototypical umami substance glutamic acid or its salt monosodium glutamate (MSG) is present in numerous savory food sources or ingredients such as kombu (edible kelp), beans, soy sauce, tomatoes, cheeses, mushrooms, and certain meats and fish. Derivatives of glutamate (Glu), other amino acids, nucleotides, and small peptides can also elicit or modulate umami taste. In addition, many potent umami tasting compounds structurally unrelated to amino acids, nucleotides, and MSG have been either synthesized or discovered as naturally occurring in plants and other substances. Over the last 20 years several receptors have been suggested to mediate umami taste, including members of the metabotropic and ionotropic Glu receptor families, and more recently, the heterodimeric G protein-coupled receptor, T1R1/T1R3. Careful assessment of representative umami tasting molecules from several different chemical classes shows activation of T1R1/T1R3 with the expected rank order of potency in cell-based assays. Moreover, 5'-ribonucleotides, molecules known to enhance the savory note of Glu, considerably enhance the effect of MSG on T1R1/T1R3 in vitro. Binding sites are found on at least 4 distinct locations on T1R1/T1R3, explaining the propensity of the receptor to being activated or modulated by many structurally distinct compounds and these binding sites allosterically interact to modulate receptor activity. Activation of T1R1/T1R3 by all known umami substances evaluated and the receptor's pharmacological properties are sufficient to explain the basic human sensory experience of savory taste and it is therefore unlikely that other receptors are involved.
Topics: Animals; Binding Sites; Humans; Nucleotides; Receptors, G-Protein-Coupled; Sodium Glutamate; Taste
PubMed: 33580387
DOI: 10.1007/164_2021_439 -
Headache Apr 2017The calcitonin gene-related peptide (CGRP) neuropeptide system is an important but still evolving target for migraine. A fundamental consideration for all of the current...
The calcitonin gene-related peptide (CGRP) neuropeptide system is an important but still evolving target for migraine. A fundamental consideration for all of the current drugs in clinical trials and for ongoing development in this area is the identity, expression pattern, and function of CGRP receptors because this knowledge informs safety and efficacy considerations. In recent years, only the calcitonin receptor-like receptor/receptor activity-modifying protein 1 (RAMP1) complex, known as the CGRP receptor, has generally been considered relevant. However, CGRP is capable of activating multiple receptors and could have more than one endogenous receptor. The recent identification of the CGRP-responsive calcitonin receptor/RAMP1 complex (AMY receptor - amylin subtype 1 receptor) in the trigeminovascular system warrants a deeper consideration of the molecular identity of CGRP receptor(s) involved in the pathophysiology, and thus potential treatment of migraine. This perspective considers some of the issues and implications.
Topics: Brain; Calcitonin Gene-Related Peptide Receptor Antagonists; Calcitonin Receptor-Like Protein; Humans; Migraine Disorders; Models, Molecular; Receptors, Calcitonin Gene-Related Peptide
PubMed: 28233915
DOI: 10.1111/head.13064 -
Journal of Ginseng Research Jan 2017Meyer, belonging to the genus of the family Araliaceae, is known for its human immune system-related effects, such as immune-boosting effects. Ginseng polysaccharides... (Review)
Review
Meyer, belonging to the genus of the family Araliaceae, is known for its human immune system-related effects, such as immune-boosting effects. Ginseng polysaccharides (GPs) are the responsible ingredient of ginseng in immunomodulation, and are classified as acidic and neutral GPs. Although GPs participate in various immune reactions including the stimulation of immune cells and production of cytokines, the precise function of GPs together with its potential receptor(s) and their signal transduction pathways have remained largely unknown. Animal lectins are carbohydrate-binding proteins that are highly specific for sugar moieties. Among many different biological functions , animal lectins especially play important roles in the immune system by recognizing carbohydrates that are found exclusively on pathogens or that are inaccessible on host cells. This review summarizes the immunological activities of GPs and the diverse roles of animal lectins in the immune system, suggesting the possibility of animal lectins as the potential receptor candidates of GPs and giving insights into the development of GPs as therapeutic biomaterials for many immunological diseases.
PubMed: 28123316
DOI: 10.1016/j.jgr.2015.12.006 -
Journal of Cardiovascular Pharmacology Jul 2017G protein-coupled receptors (GPCRs) comprise the largest family of receptors in humans. Traditional activation of GPCRs involves binding of a ligand to the receptor,... (Review)
Review
G protein-coupled receptors (GPCRs) comprise the largest family of receptors in humans. Traditional activation of GPCRs involves binding of a ligand to the receptor, activation of heterotrimeric G proteins and induction of subsequent signaling molecules. It is now known that GPCR signaling occurs through G protein-independent pathways including signaling through β-arrestin and transactivation of other receptor types. Generally, transactivation occurs when activation of one receptor leads to the activation of another receptor(s). GPCR-mediated transactivation is an essential component of GPCR signaling, as activation of other receptor types, such as receptor tyrosine kinases, allows GPCRs to expand their signal transduction and affect various cellular responses. Several mechanisms have been identified for receptor transactivation downstream of GPCRs, one of which involves activation of extracellular proteases, such as a disintegrin and metalloprotease, and matrix metalloproteases . These proteases cleave and release ligands that are then able to activate their respective receptors. A disintegrin and metalloprotease, and matrix metalloproteases can be activated via various mechanisms downstream of GPCR activation, including activation via second messenger, direct phosphorylation, or direct G protein interaction. Additional understanding of the mechanisms involved in GPCR-mediated protease activation and subsequent receptor transactivation could lead to identification of new therapeutic targets.
Topics: Animals; Extracellular Fluid; Humans; Matrix Metalloproteinases; Peptide Hydrolases; Receptors, G-Protein-Coupled; Signal Transduction; Transcriptional Activation
PubMed: 28195946
DOI: 10.1097/FJC.0000000000000475 -
Chemical Society Reviews Jul 2016Signal transduction is the primary process by which cells respond to changes in their physical and chemical environments. Cellular response is initiated through a... (Review)
Review
Signal transduction is the primary process by which cells respond to changes in their physical and chemical environments. Cellular response is initiated through a signaling protein (a receptor), which interacts with the "signal", most often a novel molecule outside or inside the cell. The mechanism of activation of the receptor is a conformational change and/or covalent modification, which then sets in motion a signaling pathway, i.e. a cascade of modification and binding events that relay and amplify the message to eventually alter the state of the cell. In reflection of this general perception, concepts such as the "second messenger" and the "phosphorylation cascade" dominate our views of signal transduction. The idea I advocate here is that the non-covalent change in protein conformation itself might serve as the initial or intermittent "signal" in the cascade, and it is often the primary event being recognized and interpreted by downstream receptor(s). This signaling principle is intertwined with many other cellular regulatory concepts, such as (pathway) allostery, conformational spread, induced folding/unfolding, conformational memory, the hierarchical assembly of complexes, and the action of regulatory chaperones and prions. By elaborating on many examples and also recent advances in experimental methodology, I show that conformational signaling, although thus far underappreciated, is a general and robust signaling principle that most of the time operates in close interplay with covalent signals in the cell.
Topics: Allosteric Regulation; Animals; Cryoelectron Microscopy; Crystallography, X-Ray; Evolution, Molecular; Humans; Magnetic Resonance Spectroscopy; Microscopy, Atomic Force; Prions; Protein Conformation; Protein Processing, Post-Translational; Proteins; Signal Transduction; Thermodynamics
PubMed: 27242242
DOI: 10.1039/c6cs00011h -
Placenta Dec 2021The (pro)renin receptor ((P)RR) is a multi-functional protein that can be proteolytically cleaved and released in a soluble form (s(P)RR). Recently, the (P)RR and s(P)RR... (Review)
Review
The (pro)renin receptor ((P)RR) is a multi-functional protein that can be proteolytically cleaved and released in a soluble form (s(P)RR). Recently, the (P)RR and s(P)RR have become of interest in pregnancy and its associated pathologies. This is because the (P)RR not only activates tissue renin angiotensin systems, but it is also an integral component of vacuolar-ATPase, activates the wingless/integrated (Wnt)/β-catenin and extracellular signal regulated kinases 1 and 2/mitogen-activated protein kinase signalling pathways, and stabilises the β subunit of pyruvate dehydrogenase. Additionally, s(P)RR is detected in plasma and urine, and maternal plasma levels are elevated in pregnancy complications including fetal growth restriction, preeclampsia and gestational diabetes mellitus. Therefore, s(P)RR has potential as a biomarker for these pregnancy pathologies. Preliminary functional findings suggest that s(P)RR may be important for regulating fluid balance, inflammation and blood pressure, all of which contribute to a successful pregnancy. The (P)RR and s(P)RR regulate pathways that are known to be important in maintaining pregnancy, however their role in the physiological context of pregnancy is poorly characterised. This review summarises the known and potential functions of the (P)RR and s(P)RR in pregnancy, and how their dysregulation may contribute to pregnancy complications. It also highlights the need for further research into the source and function of s(P)RR in pregnancy. Soluble (P)RR levels could be indicative of placental, kidney or liver dysfunction and therefore be a novel clinical biomarker, or therapeutic target, to improve the detection and treatment of pregnancy pathologies.
Topics: Animals; Diabetes, Gestational; Female; Humans; Placenta; Pre-Eclampsia; Pregnancy; Receptors, Cell Surface; Prorenin Receptor
PubMed: 34020806
DOI: 10.1016/j.placenta.2021.04.015