-
CNS Drugs Jul 2015Sphingosine 1-phosphate (S1P) receptor modulators possess a unique mechanism of action as disease-modifying therapy for multiple sclerosis (MS). Subtype 1 S1P receptors... (Review)
Review
Sphingosine 1-phosphate (S1P) receptor modulators possess a unique mechanism of action as disease-modifying therapy for multiple sclerosis (MS). Subtype 1 S1P receptors are expressed on the surfaces of lymphocytes and are important in regulating egression from lymph nodes. The S1P receptor modulators indirectly antagonize the receptor's function and sequester lymphocytes in lymph nodes. Fingolimod was the first S1P agent approved in the USA in 2010 for relapsing MS after two phase III trials (FREEDOMS and TRANSFORMS) demonstrated potent efficacy, and good safety and tolerability. Post-marketing experience, as well as a third phase III trial (FREEDOMS II), also showed favorable results. More selective S1P receptor agents-ponesimod (ACT128800), siponimod (BAF312), ozanimod (RPC1063), ceralifimod (ONO-4641), GSK2018682, and MT-1303-are still in relatively early stages of development, but phase I and II trials showed promising efficacy and safety. However, these observations have yet to be reproduced in phase III clinical trials.
Topics: Animals; Clinical Trials as Topic; Humans; Immunologic Factors; Multiple Sclerosis; Receptors, Lysosphingolipid
PubMed: 26239599
DOI: 10.1007/s40263-015-0261-z -
Molecular and Cellular Endocrinology May 2008The five somatostatin receptor subtypes, named sst1-sst5, activate both distinct and common signaling pathways and exhibit different patterns of receptor regulation.... (Review)
Review
The five somatostatin receptor subtypes, named sst1-sst5, activate both distinct and common signaling pathways and exhibit different patterns of receptor regulation. Until recently it was believed that once a particular somatostatin receptor was activated by an agonist, all the down-stream signaling and regulatory effects characteristic of that receptor subtype in that cellular environment would be triggered. Thus, differences in the actions of somatostatin analogs between tissues were attributed to variability in the nature and concentration of the sst receptor subtypes and effectors expressed in different targets. However, agonists have recently been shown to exhibit functional selectivity at individual sst receptors such that they can elicit a subset of that receptor's potential effects, a property known as biased agonism. This review will summarize the evidence for functionally selective somatostatin receptor agonists and discuss the implications and promise of these new findings.
Topics: Animals; Humans; Receptors, Somatostatin; Signal Transduction; Somatostatin
PubMed: 18006219
DOI: 10.1016/j.mce.2007.09.009 -
Cells Jan 2023The serotonin (5-HT) receptor still raises particular interest given its unique spatio-temporal pattern of expression among the serotonin receptor subtypes. It is the... (Review)
Review
The serotonin (5-HT) receptor still raises particular interest given its unique spatio-temporal pattern of expression among the serotonin receptor subtypes. It is the only serotonin receptor specifically expressed in the central nervous system, where it is detected very early in embryonic life and modulates key neurodevelopmental processes, from neuronal migration to brain circuit refinement. Its predominant localization in the primary cilium of neurons and astrocytes is also unique among the serotonin receptor subtypes. Consistent with the high expression levels of the 5-HT receptor in brain regions involved in the control of cognitive processes, it is now well-established that the pharmacological inhibition of the receptor induces pro-cognitive effects in several paradigms of cognitive impairment in rodents, including models of neurodevelopmental psychiatric disorders and neurodegenerative diseases. The 5-HT receptor can engage several signaling pathways in addition to the canonical Gs signaling, but there is still uncertainty surrounding the signaling pathways that underly its modulation of cognition, as well as how the receptor's coupling is dependent on its cellular compartmentation. Here, we describe recent findings showing how the proper subcellular localization of the receptor is achieved, how this peculiar localization determines signaling pathways engaged by the receptor, and their pathophysiological influence.
Topics: Serotonin; Receptors, Serotonin; Brain; Neurons
PubMed: 36766768
DOI: 10.3390/cells12030426 -
Journal of Virology May 2023Arthritogenic alphaviruses, including chikungunya virus (CHIKV), preferentially target joint tissues and cause chronic rheumatic disease that adversely impacts the...
Arthritogenic alphaviruses, including chikungunya virus (CHIKV), preferentially target joint tissues and cause chronic rheumatic disease that adversely impacts the quality of life of patients. Viruses enter target cells via interaction with cell surface receptor(s), which determine the viral tissue tropism and pathogenesis. Although MXRA8 is a recently identified receptor for several clinically relevant arthritogenic alphaviruses, its detailed role in the cell entry process has not been fully explored. We found that in addition to its localization on the plasma membrane, MXRA8 is present in acidic organelles, endosomes, and lysosomes. Moreover, MXRA8 is internalized into cells without a requirement for its transmembrane and cytoplasmic domains. Confocal microscopy and live cell imaging revealed that MXRA8 interacts with CHIKV at the cell surface and then enters cells along with CHIKV particles. At the moment of membrane fusion in the endosomes, many viral particles are still colocalized with MXRA8. These findings provide insight as to how MXRA8 functions in alphavirus internalization and suggest possible targets for antiviral development. The globally distributed arthritogenic alphaviruses have infected millions of humans and induce rheumatic disease, such as severe polyarthralgia/polyarthritis, for weeks to years. Alphaviruses infect target cells through receptor(s) followed by clathrin-mediated endocytosis. MXRA8 was recently identified as an entry receptor that shapes the tropism and pathogenesis for multiple arthritogenic alphaviruses, including chikungunya virus (CHIKV). Nonetheless, the exact functions of MXRA8 during the process of viral cell entry remain undetermined. Here, we have provided compelling evidence for MXRA8 as a bona fide entry receptor that mediates the uptake of alphavirus virions. Small molecules that disrupt MXRA8-dependent binding of alphaviruses or internalization steps could serve as a platform for unique classes of antiviral drugs.
Topics: Humans; Chikungunya virus; Virus Internalization; Membrane Fusion; Quality of Life; Chikungunya Fever; Rheumatic Diseases
PubMed: 37133449
DOI: 10.1128/jvi.01557-22 -
Annals of Botany Jan 2018Pathogens often secrete molecules that mimic those present in the plant host. Recent studies indicate that some of these molecules mimic plant hormones required for... (Review)
Review
BACKGROUND
Pathogens often secrete molecules that mimic those present in the plant host. Recent studies indicate that some of these molecules mimic plant hormones required for development and immunity.
SCOPE AND CONCLUSION
This Viewpoint reviews the literature on microbial molecules produced by plant pathogens that functionally mimic molecules present in the plant host. This article includes examples from nematodes, bacteria and fungi with emphasis on RaxX, a microbial protein produced by the bacterial pathogen Xanthomonas oryzae pv. oryzae. RaxX mimics a plant peptide hormone, PSY (plant peptide containing sulphated tyrosine). The rice immune receptor XA21 detects sulphated RaxX but not the endogenous peptide PSY. Studies of the RaxX/XA21 system have provided insight into both host and pathogen biology and offered a framework for future work directed at understanding how XA21 and the PSY receptor(s) can be differentially activated by RaxX and endogenous PSY peptides.
Topics: Host-Pathogen Interactions; Molecular Mimicry; Plant Diseases; Plant Immunity
PubMed: 29182721
DOI: 10.1093/aob/mcx125 -
Chemical Senses Jan 2022Controversy and misunderstanding surround the role of feeding specialization in taste receptor loss in vertebrates. We refined and tested the hypothesis that this loss...
Controversy and misunderstanding surround the role of feeding specialization in taste receptor loss in vertebrates. We refined and tested the hypothesis that this loss is caused by feeding specializations. Specifically, feeding specializations were proposed to trigger time-dependent process of taste receptor loss through deprivation of benefit of using the receptor's gustatory function. We propose that this process may be accelerated by abiotic environmental conditions or decelerated/stopped because of extragustatory functions of the receptor's protein(s). As test case we used evolution of the sweet (TAS1R2+TAS1R3) and umami (TAS1R1+TAS1R3) receptors in Carnivora (dogs, cats, and kin). We predicted these receptors' absence/presence using data on presence/absence of inactivating mutations in these receptors' genes and data from behavioral sweet/umami preference tests. We identified 20 evolutionary events of sweet (11) or umami (9) receptor loss. These events affected species with feeding specializations predicted to favor sweet/umami receptor loss (27 and 22 species, respectively). All species with feeding habits predicted to favor sweet/umami receptor retention (11 and 24, respectively) were found to retain that receptor. Six species retained the sweet (5) or umami (1) receptor despite feeding specialization predicted to favor loss of that receptor, which can be explained by the time dependence of sweet/umami receptor loss process and the possible decelerating effect of TAS1R extragustatory functions so that the sweet/umami receptor process is ongoing in these species. Our findings support the idea that feeding specialization leads to taste receptor loss and is the main if not only triggering factor for evolutionary loss of taste receptors.
Topics: Animals; Dogs; Ageusia; Taste; Taste Buds; Mutation; Carnivora
PubMed: 36433799
DOI: 10.1093/chemse/bjac033 -
Cellular and Molecular Life Sciences :... Mar 2023Membrane trafficking processes regulate the G protein-coupled receptor activity. The muscarinic acetylcholine receptors (mAChRs) are highly pursued drug targets for...
Membrane trafficking processes regulate the G protein-coupled receptor activity. The muscarinic acetylcholine receptors (mAChRs) are highly pursued drug targets for neurological diseases, but the cellular machineries that control the trafficking of these receptors remain largely elusive. Here, we revealed the role of the small GTPase Rab10 as a negative regulator for the post-activation trafficking of M4 mAChR and the underlying mechanism. We show that constitutively active Rab10 arrests the receptor within Rab5-positive early endosomes and significantly hinders the resensitization of M4-mediated Ca signaling. Mechanistically, M4 binds to Rab10-GTP, which requires the motif RKKRQMAA (R-A) within the third intracellular loop. Moreover, Rab10-GTP inactivates Arf6 by recruiting the Arf6 GTPase-activating protein, ACAP1. Strikingly, deletion of the motif R-A causes M4 to bypass the control by Rab10 and switch to the Rab4-facilitated fast recycling pathway, thus reusing the receptor. Therefore, Rab10 couples the cargo sorting and membrane trafficking regulation through cycle between GTP-bound and GDP-bound state. Our findings suggest a model that Rab10 binds to the M4 like a molecular brake and controls the receptor's transport through endosomes, thus modulating the signaling, and this regulation is specific among the mAChR subtypes.
Topics: GTP Phosphohydrolases; Cell Membrane; Receptors, Muscarinic; Signal Transduction; Endosomes; Carrier Proteins; Guanosine Triphosphate; rab GTP-Binding Proteins
PubMed: 36917255
DOI: 10.1007/s00018-023-04722-x -
Handbook of Experimental Pharmacology 2005Cannabinoids and their synthetic and endogenous analogs affect a broad range of physiological functions, including cardiovascular variables, the most important component... (Review)
Review
Cannabinoids and their synthetic and endogenous analogs affect a broad range of physiological functions, including cardiovascular variables, the most important component of their effect being profound hypotension. The mechanisms of the cardiovascular effects of cannabinoids in vivo are complex and may involve modulation of autonomic outflow in both the central and peripheral nervous systems as well as direct effects on the myocardium and vasculature. Although several lines of evidence indicate that the cardiovascular depressive effects of cannabinoids are mediated by peripherally localized CB1 receptors, recent studies provide strong support for the existence of as-yet-undefined endothelial and cardiac receptor(s) that mediate certain endocannabinoid-induced cardiovascular effects. The endogenous cannabinoid system has been recently implicated in the mechanism of hypotension associated with hemorrhagic, endotoxic, and cardiogenic shock, and advanced liver cirrhosis. Furthermore, cannabinoids have been considered as novel antihypertensive agents. A protective role of endocannabinoids in myocardial ischemia has also been documented. In this chapter, we summarize current information on the cardiovascular effects of cannabinoids and highlight the importance of these effects in a variety of pathophysiological conditions.
Topics: Animals; Cannabinoid Receptor Modulators; Cannabinoids; Cardiovascular System; Humans; Hypertension; Myocardial Contraction; Myocardial Reperfusion Injury; Receptor, Cannabinoid, CB1; Shock, Septic; TRPV Cation Channels; Vasodilation
PubMed: 16596789
DOI: 10.1007/3-540-26573-2_20 -
ELife Jul 2023Receptors signal by switching between resting (C) and active (O) shapes ('gating') under the influence of agonists. The receptor's maximum response depends on the...
Receptors signal by switching between resting (C) and active (O) shapes ('gating') under the influence of agonists. The receptor's maximum response depends on the difference in agonist binding energy, O minus C. In nicotinic receptors, efficiency (η) represents the fraction of agonist binding energy applied to a local rearrangement (an induced fit) that initiates gating. In this receptor, free energy changes in gating and binding can be interchanged by the conversion factor η. Efficiencies estimated from concentration-response curves (23 agonists, 53 mutations) sort into five discrete classes (%): 0.56 (17), 0.51(32), 0.45(13), 0.41(26), and 0.31(12), implying that there are 5 C versus O binding site structural pairs. Within each class efficacy and affinity are corelated linearly, but multiple classes hide this relationship. η unites agonist binding with receptor gating and calibrates one link in a chain of coupled domain rearrangements that comprises the allosteric transition of the protein.
Topics: Receptors, Nicotinic; Binding Sites; Mutation
PubMed: 37399234
DOI: 10.7554/eLife.86496 -
Arthritis Research 2002It is not known to what extent glucocorticoid hormones cause their anti-inflammatory actions and their undesirable side effects by the same or different molecular... (Review)
Review
It is not known to what extent glucocorticoid hormones cause their anti-inflammatory actions and their undesirable side effects by the same or different molecular mechanisms. Glucocorticoids combine with a cytoplasmic receptor that alters gene expression in two ways. One way is dependent on the receptor's binding directly to DNA and acting (positively or negatively) as a transcription factor. The other is dependent on its binding to and interfering with other transcription factors. Both mechanisms could underlie suppression of inflammation. The liganded receptor binds and inhibits the inflammatory transcription factors activator protein-1 and NF-kappaB. It also directly induces anti-inflammatory genes such as that encoding the protein inhibitor of NF-kappaB. Recent work has shown that glucocorticoids inhibit signalling in the mitogen-activated protein kinase pathways that mediate the expression of inflammatory genes. This inhibition is dependent on de novo gene expression. It is important to establish the significance of these different mechanisms for the various physiological effects of glucocorticoids, because it may be possible to produce steroid-related drugs that selectively target the inflammatory process.
Topics: Anti-Inflammatory Agents; Dexamethasone; Enzyme Inhibitors; Glucocorticoids; Humans; Inflammation; Mitogen-Activated Protein Kinases; Receptors, Glucocorticoid; Signal Transduction; Transcription Factors
PubMed: 12010562
DOI: 10.1186/ar398