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Frontiers in Immunology 2023Since the late 1970s, there has been an alarming increase in the incidence of asthma and its morbidity and mortality. Acute obstruction and inflammation of allergic... (Review)
Review
Since the late 1970s, there has been an alarming increase in the incidence of asthma and its morbidity and mortality. Acute obstruction and inflammation of allergic asthmatic airways are frequently caused by inhalation of exogenous substances such as allergens cross-linking IgE receptors expressed on the surface of the human lung mast cells (HLMC). The degree of constriction of human airways produced by identical amounts of inhaled allergens may vary from day to day and even hour to hour. Endogenous factors in the human mast cell (HMC)'s microenvironment during allergen exposure may markedly modulate the degranulation response. An increase in allergic responsiveness may significantly enhance bronchoconstriction and breathlessness. This review focuses on the role that the ubiquitous endogenous purine nucleotide, extracellular adenosine 5'-triphosphate (ATP), which is a component of the damage-associated molecular patterns, plays in mast cells' physiology. ATP activates P2 purinergic cell-surface receptors (P2R) to trigger signaling cascades resulting in heightened inflammatory responses. ATP is the most potent enhancer of IgE-mediated HLMC degranulation described to date. Current knowledge of ATP as it relates to targeted receptor(s) on HMC along with most recent studies exploring HMC post-receptor activation pathways are discussed. In addition, the reviewed studies may explain why brief, minimal exposures to allergens (e.g., dust, cat, mouse, and grass) can unpredictably lead to intense clinical reactions. Furthermore, potential therapeutic approaches targeting ATP-related enhancement of allergic reactions are presented.
Topics: Humans; Animals; Mice; Mast Cells; Signal Transduction; Adenosine Triphosphate; Asthma; Lung; Hypersensitivity; Allergens; Receptors, Purinergic P2
PubMed: 37868982
DOI: 10.3389/fimmu.2023.1216580 -
Frontiers in Physiology 2023Whether GPCRs support the sensing of temperature as well as other chemical and physical modalities is not well understood. Extracellular Ca concentration (Ca )...
Whether GPCRs support the sensing of temperature as well as other chemical and physical modalities is not well understood. Extracellular Ca concentration (Ca ) modulates core body temperature and the firing rates of temperature-sensitive CNS neurons, and hypocalcemia provokes childhood seizures. However, it is not known whether these phenomena are mediated by Ca -sensing GPCRs, including the calcium-sensing receptor (CaSR). In favor of the hypothesis, CaSRs are expressed in hypothalamic regions that support core temperature regulation, and autosomal dominant hypocalcemia, due to CaSR activating mutations, is associated with childhood seizures. Herein, we tested whether CaSR-dependent signaling is temperature sensitive using an established model system, CaSR-expressing HEK-293 cells. We found that the frequency of Ca -induced Ca oscillations but not the integrated response was linearly dependent on temperature in a pathophysiologically relevant range. Chimeric receptor analysis showed that the receptor's C-terminus is required for temperature-dependent modulation and experiments with the PKC inhibitor GF109203X and CaSR mutants T888A and T888M, which eliminate a key phosphorylation site, demonstrated the importance of repetitive phosphorylation and dephosphorylation. CaSRs mediate temperature-sensing and the mechanism, dependent upon repetitive phosphorylation and dephosphorylation, suggests that GPCRs more generally contribute to temperature-sensing.
PubMed: 36818436
DOI: 10.3389/fphys.2023.1117352 -
Soft Matter Aug 2023Receptor-mediated endocytosis (RME) is a highly complex process carried out by bioparticles, such as viruses and drug carriers, to enter cells. The discovery of both...
Receptor-mediated endocytosis (RME) is a highly complex process carried out by bioparticles, such as viruses and drug carriers, to enter cells. The discovery of both clathrin-dependent and clathrin-free pathways makes the RME process even more intriguing. Numerical models have been developed to facilitate the exploration of the process. However, the impacts of the receptor properties on RME have been less studied partially due to the oversimplifications of the receptor models. In this paper, we implement a stochastic model to systematically investigate the effects of mechanical (receptor flexure), geometrical (receptor length) and biochemical (ligand-receptor cutoff) properties of receptors, on RME with and without the existence of clathrin. Our simulation results show that the receptor's flexural rigidity plays an important role in RME with clathrin. There is a threshold beyond which particle internalization will not occur. Without clathrin, it is very difficult to achieve complete endocytosis with ligand-receptor interactions alone. A shorter receptor length and longer ligand-receptor reaction cutoff promote the formation of ligand-receptor bonds and facilitate particle internalization. Complete internalization can only be obtained with an extremely short receptor length and long reaction cutoff. Therefore, there are most likely some additional mechanisms to drive the membrane deformation in clathrin-free RME. Our results yield important fundamental insights into RME and provide crucial guidance when correlating the simulation results with experimental observations.
Topics: Ligands; Endocytosis; Clathrin
PubMed: 37483086
DOI: 10.1039/d3sm00149k -
International Journal of Molecular... Dec 2020The vast majority of the literature on the aryl hydrocarbon receptor is concerned with its functions in xenobiotic detoxification. However, in the course of evolution,... (Review)
Review
The vast majority of the literature on the aryl hydrocarbon receptor is concerned with its functions in xenobiotic detoxification. However, in the course of evolution, this receptor had to have physiological (rather than toxicological) functions. Our aim was to review the aryl hydrocarbon receptor's role in the physiological functions involved in aging. This study was performed by searching the MEDLINE and Google Academic databases. A total of 34 articles were selected that focused specifically on the aryl hydrocarbon receptor and aging, the aryl hydrocarbon receptor and physiological functions, and the combination of both. This receptor's main physiological functions (mediated by the modulation of gene expression) were cell regeneration, the immune reaction, intestinal homeostasis, and cell proliferation. Furthermore, it was shown that the loss of this receptor led to premature aging. This process may be caused by the dysregulation of hematopoietic stem cells, loss of glucose and lipid homeostasis, increase in inflammation, and deterioration of the brain. We conclude that the aryl hydrocarbon receptor, apart from its well-established role in xenobiotic detoxication, plays an important role in physiological functions and in the aging process. Modulation of the signaling pathway of this receptor could be a therapeutic target of interest in aging.
Topics: Aging; Aging, Premature; Animals; Humans; Receptors, Aryl Hydrocarbon; Signal Transduction; Xenobiotics
PubMed: 33396477
DOI: 10.3390/ijms22010374 -
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 -
British Journal of Pharmacology Nov 2022Oxysterols have gained attention over the last decades and are now considered as fully fledged bioactive lipids. The study of their levels in several conditions,... (Review)
Review
Oxysterols have gained attention over the last decades and are now considered as fully fledged bioactive lipids. The study of their levels in several conditions, including atherosclerosis, obesity and neurodegenerative diseases, led to a better understanding of their involvement in (patho)physiological processes such as inflammation and immunity. For instance, the characterization of the cholesterol-7α,25-dihydroxycholesterol/GPR183 axis and its implication in immunity represents an important step in the oxysterome study. Besides this axis, others were identified as important in several inflammatory pathologies (such as colitis, lung inflammation and atherosclerosis). However, the oxysterome is a complex system notably due to a redundancy of metabolic enzymes and a wide range of receptors. Indeed, deciphering oxysterol roles and identifying the potential receptor(s) involved in a given pathology remain challenging. Oxysterol properties are very diverse, but most of them could be connected by a common component: inflammation. Here, we review the implication of oxysterol receptors in inflammatory diseases. LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.
Topics: Atherosclerosis; Colitis; Humans; Inflammation; Oxysterols
PubMed: 33817775
DOI: 10.1111/bph.15479 -
ACS Chemical Biology Feb 2021Intercellular signaling events mediated by neuropeptides and peptide hormones represent important targets for both basic science and drug discovery. For many bioactive... (Review)
Review
Intercellular signaling events mediated by neuropeptides and peptide hormones represent important targets for both basic science and drug discovery. For many bioactive peptides, the protein receptors that transmit information across the receiving cell membrane are not known, severely limiting these signaling pathways as potential therapeutic targets. Identifying the receptor(s) for a given peptide of interest is complicated by several factors. Most notably, cell-cell signaling peptides are generated through dynamic biosynthetic pathways, can act on many different families of receptor proteins, and can participate in complex ligand-receptor interactions that extend beyond a simple one-to-one archetype. Here, we discuss recent methodological advances to identify signaling partners for bioactive peptides. Recent efforts have centered on methods to identify candidate receptors via transcript expression, methods to match peptide-receptor pairs through high throughput screening, and methods to capture direct ligand-receptor interactions using chemical probes. Future applications of the receptor identification approaches discussed here, as well as technical advancements to address their limitations, promise to lead to a greater understanding of how cells communicate to deliver complex physiologies. Importantly, such advancements will likely provide novel targets for the treatment of human diseases within the central nervous and endocrine systems.
Topics: Animals; Humans; Ligands; Machine Learning; Molecular Probes; Neuropeptides; Peptide Hormones; Receptors, G-Protein-Coupled; Receptors, Neuropeptide
PubMed: 33539706
DOI: 10.1021/acschembio.0c00950 -
European Journal of Clinical... Apr 2021Recently, various studies have shown that angiotensin-converting enzyme 2 (ACE2) acts as the "doorknob" that can be bound by the spike protein of severe acute... (Review)
Review
Recently, various studies have shown that angiotensin-converting enzyme 2 (ACE2) acts as the "doorknob" that can be bound by the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which conduces to its entrance to the host cells, and plays an important role in corona virus disease 2019 (COVID-19). This paper aims to collect and sorts out the existing drugs, which exert the ability to block the binding of S protein and ACE2 so as to provide directions for the later drug development. By reviewing the existing literature, we expound the pathogenesis of SARS-CoV-2 from the perspective of S protein and ACE2 binding, and summarize the drugs and compounds that can interfere with the interaction of spike protein and ACE2 receptor from different ways. We summarized five kinds of substances, including peptide P6, griffithsin, hr2p analogs, EK1, vaccine, monoclonal antibody, cholesterol-depleting agents, and extracts from traditional Chinese medicine. They can fight SARS-CoV-2 by specifically binding to ACE2 receptor, S protein, or blocking membrane fusion between the host and virus. ACE2 is the key point for SARS-CoV-2 to enter the cells, and it is also the focus of drug intervention. Our drug summary on this pathomechanism is expected to provide ideas for the drug research on SARS-CoV-2 and help to develop anti-coronavirus drugs of broad spectrum for future epidemics.
Topics: Angiotensin-Converting Enzyme 2; Drug Evaluation, Preclinical; Humans; Receptors, Coronavirus; SARS-CoV-2; Spike Glycoprotein, Coronavirus; COVID-19 Drug Treatment
PubMed: 33034780
DOI: 10.1007/s10096-020-04048-7 -
Heliyon Aug 2019Uridine 5'-triphosphate (UTP) exerts a positive inotropic effect (PIE) in isolated electrically driven isolated right atrial trabeculae carneae from patients undergoing... (Review)
Review
Uridine 5'-triphosphate (UTP) exerts a positive inotropic effect (PIE) in isolated electrically driven isolated right atrial trabeculae carneae from patients undergoing heart surgery. This review discusses some aspects of the current knowledge on the putative receptor(s) involved and the potential biochemical transduction steps leading to the PIE.
PubMed: 31406941
DOI: 10.1016/j.heliyon.2019.e02197 -
Journal of Virology Feb 2023Rabies virus (RABV) is a prototypical neurotropic virus that causes rabies in human and animals with an almost 100% mortality rate. Once RABV enters the central nervous...
Rabies virus (RABV) is a prototypical neurotropic virus that causes rabies in human and animals with an almost 100% mortality rate. Once RABV enters the central nervous system, no treatment is proven to prevent death. RABV glycoprotein (G) interacts with cell surface receptors and then enters cells via clathrin-mediated endocytosis (CME); however, the key host factors involved remain largely unknown. Here, we identified transferrin receptor 1 (TfR1), a classic receptor that undergoes CME, as an entry factor for RABV. TfR1 interacts with RABV G and is involved in the endocytosis of RABV. An antibody against TfR1 or the TfR1 ectodomain soluble protein significantly blocked RABV infection in HEK293 cells, N2a cells, and mouse primary neuronal cells. We further found that the endocytosis of TfR1 is coupled with the endocytosis of RABV and that TfR1 and RABV are transported to early and late endosomes. Our results suggest that RABV hijacks the transport pathway of TfR1 for entry, thereby deepening our understanding of the entry mechanism of RABV. For most viruses, cell entry involves engagement with many distinct plasma membrane components, each of which is essential. After binding to its specific receptor(s), rabies virus (RABV) enters host cells through the process of clathrin-mediated endocytosis. However, whether the receptor-dependent clathrin-mediated endocytosis of RABV requires other plasma membrane components remain largely unknown. Here, we demonstrate that transferrin receptor 1 (TfR1) is a functional entry factor for RABV infection. The endocytosis of RABV is coupled with the endocytosis of TfR1. Our results indicate that RABV hijacks the transport pathway of TfR1 for entry, which deepens our understanding of the entry mechanism of RABV.
Topics: Animals; Humans; Mice; Clathrin; HEK293 Cells; Rabies; Rabies virus; Receptors, Transferrin; Virus Internalization; Cell Line; Endocytosis
PubMed: 36779762
DOI: 10.1128/jvi.01612-22