Pub Date : 2023-06-06DOI: 10.3390/receptors2020010
D. Steverding
The cycle number (nc) of a recycling receptor is defined as the average number of round trips (cell surface–endosome–cell surface) the receptor can make before it is degraded. This characteristic parameter of recycling receptors can be easily determined from the receptor’s half-life (t½, the time in which 50% of the receptor is degraded) and cycling time (Tc, the time a receptor needs to complete a round trip). Relationship analyses revealed that nc increases linearly with increasing t½ and decreases exponentially with increasing Tc. For commonly observed t½ and Tc values, it was calculated that recycling receptors have nc values of <300. In addition, it was found that recycling receptors in cancer cells have generally smaller nc values (<100), whereas recycling receptors in normal cells have larger nc values (>100). Based on this latter finding, the cycle number nc may be a useful criterion for distinguishing between cancer and normal cells.
{"title":"Cycle Numbers of Cell Surface Recycling Receptors","authors":"D. Steverding","doi":"10.3390/receptors2020010","DOIUrl":"https://doi.org/10.3390/receptors2020010","url":null,"abstract":"The cycle number (nc) of a recycling receptor is defined as the average number of round trips (cell surface–endosome–cell surface) the receptor can make before it is degraded. This characteristic parameter of recycling receptors can be easily determined from the receptor’s half-life (t½, the time in which 50% of the receptor is degraded) and cycling time (Tc, the time a receptor needs to complete a round trip). Relationship analyses revealed that nc increases linearly with increasing t½ and decreases exponentially with increasing Tc. For commonly observed t½ and Tc values, it was calculated that recycling receptors have nc values of <300. In addition, it was found that recycling receptors in cancer cells have generally smaller nc values (<100), whereas recycling receptors in normal cells have larger nc values (>100). Based on this latter finding, the cycle number nc may be a useful criterion for distinguishing between cancer and normal cells.","PeriodicalId":74651,"journal":{"name":"Receptors (Basel, Switzerland)","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83628167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-05-11DOI: 10.3390/receptors2020009
R. Nault, Giovan N. Cholico, T. Zacharewski
Communication between cells is essential in maintaining homeostasis. The persistent disruption of cell–cell communication by environmental contaminants contributes to progressive disease and toxicity. In this study, single-nuclei RNA sequencing (snRNAseq) data was used to examine dose-dependent cell-specific changes in cell–cell communication associated with the development of liver pathologies following the persistent activation of the aryl hydrocarbon receptor (AHR) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Published hepatic snRNAseq data from male mice gavaged with sesame-oil vehicle or TCDD every 4 days for 28 days was used to assess the AHR-mediated disruption of ligand–receptor interactions. Analysis identified that portal fibroblasts and liver sinusoidal endothelial cells contributed the most ligand–receptor pairs at doses < 0.3μg/kg TCDD. Doses ≥ 0.3 μg/kg TCDD increased the putative intercellular communication between hepatocytes and hepatic stellate cells. In control livers, interactions primarily consisted of protease-activated receptor (PAR) signaling. TCDD treatment increased the number of active signaling pathways. Within hepatocytes, neuregulin signaling was induced, activating the NRG1–ERBB4 ligand axis, consistent with AHR genomic enrichment at dioxin response elements in a published chromatin immunoprecipitation sequencing (ChIP-seq) dataset, which suggested a direct regulation. Collectively, the results suggest that the disruption of cell signaling may play a central role in TCDD-elicited liver pathologies.
{"title":"Analysis of Cell–Cell Communication by Single-Nuclei RNA Sequencing Identifies AHR-Mediated Induction of NRG-ERBB Signaling","authors":"R. Nault, Giovan N. Cholico, T. Zacharewski","doi":"10.3390/receptors2020009","DOIUrl":"https://doi.org/10.3390/receptors2020009","url":null,"abstract":"Communication between cells is essential in maintaining homeostasis. The persistent disruption of cell–cell communication by environmental contaminants contributes to progressive disease and toxicity. In this study, single-nuclei RNA sequencing (snRNAseq) data was used to examine dose-dependent cell-specific changes in cell–cell communication associated with the development of liver pathologies following the persistent activation of the aryl hydrocarbon receptor (AHR) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Published hepatic snRNAseq data from male mice gavaged with sesame-oil vehicle or TCDD every 4 days for 28 days was used to assess the AHR-mediated disruption of ligand–receptor interactions. Analysis identified that portal fibroblasts and liver sinusoidal endothelial cells contributed the most ligand–receptor pairs at doses < 0.3μg/kg TCDD. Doses ≥ 0.3 μg/kg TCDD increased the putative intercellular communication between hepatocytes and hepatic stellate cells. In control livers, interactions primarily consisted of protease-activated receptor (PAR) signaling. TCDD treatment increased the number of active signaling pathways. Within hepatocytes, neuregulin signaling was induced, activating the NRG1–ERBB4 ligand axis, consistent with AHR genomic enrichment at dioxin response elements in a published chromatin immunoprecipitation sequencing (ChIP-seq) dataset, which suggested a direct regulation. Collectively, the results suggest that the disruption of cell signaling may play a central role in TCDD-elicited liver pathologies.","PeriodicalId":74651,"journal":{"name":"Receptors (Basel, Switzerland)","volume":"82 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83745534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-04-14DOI: 10.3390/receptors2020008
E. Cecon, J. Boutin, R. Jockers
Melatonin, the hormone of darkness, is secreted in minute amounts during the night and is virtually undetectable during the day. Melatonin mainly acts on high-affinity G protein-coupled receptors. The present review will trace the path of the discovery of melatonin receptors from their cloning, expression and purification to the development of recent radioactive and fluorescent tracers. We will then report on the state-of-the-art of melatonin receptor functional properties, including ligand bias and system bias due to receptor-associated proteins and receptor heteromers. Currently available antibodies raised against melatonin receptors will be critically reviewed here for the first time. The review will close with future perspectives in terms of the discovery of allosteric ligands and the in vivo validation of a range of melatonin receptor-associated signaling complexes to improve future drug development.
{"title":"Molecular Characterization and Pharmacology of Melatonin Receptors in Animals","authors":"E. Cecon, J. Boutin, R. Jockers","doi":"10.3390/receptors2020008","DOIUrl":"https://doi.org/10.3390/receptors2020008","url":null,"abstract":"Melatonin, the hormone of darkness, is secreted in minute amounts during the night and is virtually undetectable during the day. Melatonin mainly acts on high-affinity G protein-coupled receptors. The present review will trace the path of the discovery of melatonin receptors from their cloning, expression and purification to the development of recent radioactive and fluorescent tracers. We will then report on the state-of-the-art of melatonin receptor functional properties, including ligand bias and system bias due to receptor-associated proteins and receptor heteromers. Currently available antibodies raised against melatonin receptors will be critically reviewed here for the first time. The review will close with future perspectives in terms of the discovery of allosteric ligands and the in vivo validation of a range of melatonin receptor-associated signaling complexes to improve future drug development.","PeriodicalId":74651,"journal":{"name":"Receptors (Basel, Switzerland)","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87898846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-03-07DOI: 10.3390/receptors2010007
I. Nalvarte, P. Antonson
Estrogens play a crucial role in sexual development and fertility as well as many other physiological processes, and it is estrogen receptors that mediate the physiological responses. To study the role of the estrogen receptors in these processes, several genetic mouse models have been developed using different strategies, which also in some cases yield different results. Here, we summarize the models that have been made and their impact on fertility in relation to known cases of human estrogen receptor mutations.
{"title":"Estrogen Receptor Knockout Mice and Their Effects on Fertility","authors":"I. Nalvarte, P. Antonson","doi":"10.3390/receptors2010007","DOIUrl":"https://doi.org/10.3390/receptors2010007","url":null,"abstract":"Estrogens play a crucial role in sexual development and fertility as well as many other physiological processes, and it is estrogen receptors that mediate the physiological responses. To study the role of the estrogen receptors in these processes, several genetic mouse models have been developed using different strategies, which also in some cases yield different results. Here, we summarize the models that have been made and their impact on fertility in relation to known cases of human estrogen receptor mutations.","PeriodicalId":74651,"journal":{"name":"Receptors (Basel, Switzerland)","volume":"154 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73456419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-03-01Epub Date: 2023-01-04DOI: 10.3390/receptors2010001
Nikhil Y Patil, Jacob E Friedman, Aditya D Joshi
Numerous nuclear receptors including farnesoid X receptor, liver X receptor, peroxisome proliferator-activated receptors, pregnane X receptor, hepatic nuclear factors have been extensively studied within the context of non-alcoholic fatty liver disease (NAFLD). Following the first description of the Aryl hydrocarbon Receptor (AhR) in the 1970s and decades of research which unveiled its role in toxicity and pathophysiological processes, the functional significance of AhR in NAFLD has not been completely decoded. Recently, multiple research groups have utilized a plethora of in vitro and in vivo models that mimic NAFLD pathology to investigate the functional significance of AhR in fatty liver disease. This review provides a comprehensive account of studies describing both the beneficial and possible detrimental role of AhR in NAFLD. A plausible reconciliation for the paradox indicating AhR as a 'double-edged sword' in NAFLD is discussed. Finally, understanding AhR ligands and their signaling in NAFLD will facilitate us to probe AhR as a potential drug target to design innovative therapeutics against NAFLD in the near future.
{"title":"Role of Hepatic Aryl Hydrocarbon Receptor in Non-Alcoholic Fatty Liver Disease.","authors":"Nikhil Y Patil, Jacob E Friedman, Aditya D Joshi","doi":"10.3390/receptors2010001","DOIUrl":"10.3390/receptors2010001","url":null,"abstract":"<p><p>Numerous nuclear receptors including farnesoid X receptor, liver X receptor, peroxisome proliferator-activated receptors, pregnane X receptor, hepatic nuclear factors have been extensively studied within the context of non-alcoholic fatty liver disease (NAFLD). Following the first description of the Aryl hydrocarbon Receptor (AhR) in the 1970s and decades of research which unveiled its role in toxicity and pathophysiological processes, the functional significance of AhR in NAFLD has not been completely decoded. Recently, multiple research groups have utilized a plethora of in vitro and in vivo models that mimic NAFLD pathology to investigate the functional significance of AhR in fatty liver disease. This review provides a comprehensive account of studies describing both the beneficial and possible detrimental role of AhR in NAFLD. A plausible reconciliation for the paradox indicating AhR as a 'double-edged sword' in NAFLD is discussed. Finally, understanding AhR ligands and their signaling in NAFLD will facilitate us to probe AhR as a potential drug target to design innovative therapeutics against NAFLD in the near future.</p>","PeriodicalId":74651,"journal":{"name":"Receptors (Basel, Switzerland)","volume":"2 1","pages":"1-15"},"PeriodicalIF":0.0,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10240927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9623114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-03-01DOI: 10.3390/receptors2010006
Anthony M. Franchini, Keegan L. Vaughan, Soumyaroop Bhattacharya, Kameshwar P. Singh, Thomas A. Gasiewicz, B. Paige Lawrence
Recent evidence suggests that the environment-sensing transcription factor aryl hydrocarbon receptor (AHR) is an important regulator of hematopoiesis. Yet, the mechanisms and extent of AHR-mediated regulation within the most primitive hematopoietic cells, hematopoietic stem and progenitor cells (HSPCs), are poorly understood. Through a combination of transcriptomic and flow cytometric approaches, this study provides new insight into how the AHR influences hematopoietic stem and progenitor cells. Comparative analysis of intraphenotypic transcriptomes of hematopoietic stem cells (HSCs) and multipotent progenitor (MPP) cells from AHR knockout (AHR KO) and wild type mice revealed significant differences in gene expression patterns. Notable among these were differences in expression of cell cycle regulators, specifically an enrichment of G2/M checkpoint genes when Ahr was absent. This included the regulator Aurora A kinase (Aurka, AurA). Analysis of AurA protein levels in HSPC subsets using flow cytometry, in combination with inducible AHR KO or in vivo AHR antagonism, showed that attenuation of AHR increased levels of AurA in HSCs and lineage-biased MPP cells. Overall, these data highlight a potential novel mechanism by which AHR controls HSC homeostasis and HSPC differentiation. These findings advance the understanding of how AHR influences and regulates primitive hematopoiesis.
{"title":"Impact of the Aryl Hydrocarbon Receptor on Aurora A Kinase and the G2/M Phase Pathway in Hematopoietic Stem and Progenitor Cells","authors":"Anthony M. Franchini, Keegan L. Vaughan, Soumyaroop Bhattacharya, Kameshwar P. Singh, Thomas A. Gasiewicz, B. Paige Lawrence","doi":"10.3390/receptors2010006","DOIUrl":"https://doi.org/10.3390/receptors2010006","url":null,"abstract":"Recent evidence suggests that the environment-sensing transcription factor aryl hydrocarbon receptor (AHR) is an important regulator of hematopoiesis. Yet, the mechanisms and extent of AHR-mediated regulation within the most primitive hematopoietic cells, hematopoietic stem and progenitor cells (HSPCs), are poorly understood. Through a combination of transcriptomic and flow cytometric approaches, this study provides new insight into how the AHR influences hematopoietic stem and progenitor cells. Comparative analysis of intraphenotypic transcriptomes of hematopoietic stem cells (HSCs) and multipotent progenitor (MPP) cells from AHR knockout (AHR KO) and wild type mice revealed significant differences in gene expression patterns. Notable among these were differences in expression of cell cycle regulators, specifically an enrichment of G2/M checkpoint genes when Ahr was absent. This included the regulator Aurora A kinase (Aurka, AurA). Analysis of AurA protein levels in HSPC subsets using flow cytometry, in combination with inducible AHR KO or in vivo AHR antagonism, showed that attenuation of AHR increased levels of AurA in HSCs and lineage-biased MPP cells. Overall, these data highlight a potential novel mechanism by which AHR controls HSC homeostasis and HSPC differentiation. These findings advance the understanding of how AHR influences and regulates primitive hematopoiesis.","PeriodicalId":74651,"journal":{"name":"Receptors (Basel, Switzerland)","volume":"19 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136246131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-02-04DOI: 10.3390/receptors2010004
J. Banères, Thomas Botzanowski, J. Boutin, Barbara Calamini, Jérôme Castel, L. Catoire, S. Cianférani, C. Demesmay, G. Ferguson, G. Ferry, J. Kniazeff, I. Krimm, Thierry Langer, G. Lebon, M. Ley, M. Nyerges, Magali Schwob, C. Vénien-Bryan, R. Wagner, G. Zeder‐Lutz, Claudia Zilian-Stohrer
In an effort to provide an overview of the biophysical approaches used to study G-protein-coupled receptors, we chose to consider the adenosine A2A receptor as a model, as it is widely reported in the literature to explore the way GPCRs are studied nowadays. After a brief introduction of the receptor, we gathered descriptions of the various tools used to investigate the pharmacology and structure of the A2A receptor. We began by describing the key developments which have led to successful studies of GPCRs including the cloning, expression and purification of A2A, and the subsequent characterizations including quality control, binding and functional studies that have been necessary for the further understanding of the receptor. Then, we reviewed the reconstitution of A2A into nanodiscs as well as the use of this biological material in structural mass spectrometry, NMR, calorimetry and various other approaches to gain not only information about the structure and function of A2A, but also the dynamics of the receptor and the tools necessary to pursue such investigations. The body of techniques presented herein are applicable to all GPCRs amenable to purification.
{"title":"Biophysical Dissection of Isolated GPCRs: The Adenosine A2A Receptor under the Bistouries","authors":"J. Banères, Thomas Botzanowski, J. Boutin, Barbara Calamini, Jérôme Castel, L. Catoire, S. Cianférani, C. Demesmay, G. Ferguson, G. Ferry, J. Kniazeff, I. Krimm, Thierry Langer, G. Lebon, M. Ley, M. Nyerges, Magali Schwob, C. Vénien-Bryan, R. Wagner, G. Zeder‐Lutz, Claudia Zilian-Stohrer","doi":"10.3390/receptors2010004","DOIUrl":"https://doi.org/10.3390/receptors2010004","url":null,"abstract":"In an effort to provide an overview of the biophysical approaches used to study G-protein-coupled receptors, we chose to consider the adenosine A2A receptor as a model, as it is widely reported in the literature to explore the way GPCRs are studied nowadays. After a brief introduction of the receptor, we gathered descriptions of the various tools used to investigate the pharmacology and structure of the A2A receptor. We began by describing the key developments which have led to successful studies of GPCRs including the cloning, expression and purification of A2A, and the subsequent characterizations including quality control, binding and functional studies that have been necessary for the further understanding of the receptor. Then, we reviewed the reconstitution of A2A into nanodiscs as well as the use of this biological material in structural mass spectrometry, NMR, calorimetry and various other approaches to gain not only information about the structure and function of A2A, but also the dynamics of the receptor and the tools necessary to pursue such investigations. The body of techniques presented herein are applicable to all GPCRs amenable to purification.","PeriodicalId":74651,"journal":{"name":"Receptors (Basel, Switzerland)","volume":"275 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76511930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-02-01DOI: 10.3390/receptors2010003
Scott Widmann, Shivangi Srivastava, Chin-Yo Lin
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a high mortality rate and few effective treatments. A growing area of cancer therapeutics seeks to exploit the metabolic dysregulation of cancer cells, such as glucose, amino acid, and fatty acid metabolism, to selectively target malignant cells. As ligand-dependent transcription factors and critical regulators of metabolism, liver X receptors (LXRs) are amenable to small-molecule targeting for such purposes. We have profiled the transcriptomic, metabolomic, and cytotoxic effects of a newly discovered small-molecule LXR modulator, GAC0003A4 (3A4), in PDAC cell lines. On the transcriptomic level, marked changes in gene expression were observed, including downregulation of LXR target genes and pathways. Gene set enrichment analysis determined downregulation of several metabolic pathways, such as fatty acid and cholesterol metabolism, while upregulated pathways involved TNFα/NF-κB and other stress-induced processes. Metabolomic analyses revealed altered metabolites in several pathways, the most enriched categories being lipids and amino acid metabolites, while phospholipids and sphingolipids, including ceramides, were also found to be significantly altered. Insights from transcriptomic and metabolomic studies helped guide the determination of alterations in cholesterol and ceramides as integral to the antiproliferative mechanisms of 3A4. Additionally, a concurrent programmed cell death mechanism involving apoptosis and necroptosis was shown to be activated. These studies provide novel insights into the effects of LXR modulation on gene expression, metabolism, and cell death induction in PDAC cells. The metabolic and cytotoxic effects of LXR modulation on the PDAC cell lines used in this study could also aid in the design and application of drugs to target other refractory cancers.
{"title":"A Novel Liver X Receptor Inverse Agonist Impairs Cholesterol and Phospholipid Metabolism and Induces Apoptosis and Necroptosis in Pancreatic Ductal Adenocarcinoma Cells","authors":"Scott Widmann, Shivangi Srivastava, Chin-Yo Lin","doi":"10.3390/receptors2010003","DOIUrl":"https://doi.org/10.3390/receptors2010003","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a high mortality rate and few effective treatments. A growing area of cancer therapeutics seeks to exploit the metabolic dysregulation of cancer cells, such as glucose, amino acid, and fatty acid metabolism, to selectively target malignant cells. As ligand-dependent transcription factors and critical regulators of metabolism, liver X receptors (LXRs) are amenable to small-molecule targeting for such purposes. We have profiled the transcriptomic, metabolomic, and cytotoxic effects of a newly discovered small-molecule LXR modulator, GAC0003A4 (3A4), in PDAC cell lines. On the transcriptomic level, marked changes in gene expression were observed, including downregulation of LXR target genes and pathways. Gene set enrichment analysis determined downregulation of several metabolic pathways, such as fatty acid and cholesterol metabolism, while upregulated pathways involved TNFα/NF-κB and other stress-induced processes. Metabolomic analyses revealed altered metabolites in several pathways, the most enriched categories being lipids and amino acid metabolites, while phospholipids and sphingolipids, including ceramides, were also found to be significantly altered. Insights from transcriptomic and metabolomic studies helped guide the determination of alterations in cholesterol and ceramides as integral to the antiproliferative mechanisms of 3A4. Additionally, a concurrent programmed cell death mechanism involving apoptosis and necroptosis was shown to be activated. These studies provide novel insights into the effects of LXR modulation on gene expression, metabolism, and cell death induction in PDAC cells. The metabolic and cytotoxic effects of LXR modulation on the PDAC cell lines used in this study could also aid in the design and application of drugs to target other refractory cancers.","PeriodicalId":74651,"journal":{"name":"Receptors (Basel, Switzerland)","volume":"88 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79978553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-04DOI: 10.3390/receptors2010002
J. Boutin, J. Leprince
Intuitively, it is easy to understand why we search for G protein-coupled receptor (GPCR) antagonists. It is obviously to block a functionality of a specific receptor potentially linked to some aspects of disease. Whether by focused research or by serendipity, many drugs were discovered in the last century that function as antagonist at a precise receptor. A current idea is that at least half of the drugs on the market are antagonist ligands of GPCRs. Then, why are we searching for alternative receptor agonists while the endogenous activating molecule is known? In the present commentary we try to rationalize these fields of research, since they proved to be very successful over the years, with receptor pharmacology populated with dozens of alternative agonists, particularly to bioaminergic receptors, and to a lesser extent to peptidergic ones. However, the action of such compounds is not well-characterized: are they surrogates to the endogenous agonist, and if yes in which context and for which purpose? The present essay is a reflection on this subject that leads to fundamental interrogations of our understanding of GPCR roles and functions.
{"title":"Why Search for Alternative GPCR Agonists?","authors":"J. Boutin, J. Leprince","doi":"10.3390/receptors2010002","DOIUrl":"https://doi.org/10.3390/receptors2010002","url":null,"abstract":"Intuitively, it is easy to understand why we search for G protein-coupled receptor (GPCR) antagonists. It is obviously to block a functionality of a specific receptor potentially linked to some aspects of disease. Whether by focused research or by serendipity, many drugs were discovered in the last century that function as antagonist at a precise receptor. A current idea is that at least half of the drugs on the market are antagonist ligands of GPCRs. Then, why are we searching for alternative receptor agonists while the endogenous activating molecule is known? In the present commentary we try to rationalize these fields of research, since they proved to be very successful over the years, with receptor pharmacology populated with dozens of alternative agonists, particularly to bioaminergic receptors, and to a lesser extent to peptidergic ones. However, the action of such compounds is not well-characterized: are they surrogates to the endogenous agonist, and if yes in which context and for which purpose? The present essay is a reflection on this subject that leads to fundamental interrogations of our understanding of GPCR roles and functions.","PeriodicalId":74651,"journal":{"name":"Receptors (Basel, Switzerland)","volume":"51 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80064194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-11-17DOI: 10.3390/receptors1010006
I. Demirsoy, G. Ferrari
Neurokinin-1 receptor (NK1R) signaling pathways play a crucial role in a number of biological processes in the eye. Specifically, in the ocular surface, their activity modulates epithelial integrity, inflammation, and generation of pain, while they have a role in visual processing in the retina. The NK1R is broadly expressed in the eye, in both ocular and non-ocular cells, such as leukocytes and neurons. In this review, we will discuss the roles of neurokinin-1 receptors and substance P (SP) in the physiopathology of eye disorders. Finally, we will review and highlight the therapeutic benefits of NK1R antagonists in the treatment of ocular diseases.
{"title":"The NK-1 Receptor Signaling: Distribution and Functional Relevance in the Eye","authors":"I. Demirsoy, G. Ferrari","doi":"10.3390/receptors1010006","DOIUrl":"https://doi.org/10.3390/receptors1010006","url":null,"abstract":"Neurokinin-1 receptor (NK1R) signaling pathways play a crucial role in a number of biological processes in the eye. Specifically, in the ocular surface, their activity modulates epithelial integrity, inflammation, and generation of pain, while they have a role in visual processing in the retina. The NK1R is broadly expressed in the eye, in both ocular and non-ocular cells, such as leukocytes and neurons. In this review, we will discuss the roles of neurokinin-1 receptors and substance P (SP) in the physiopathology of eye disorders. Finally, we will review and highlight the therapeutic benefits of NK1R antagonists in the treatment of ocular diseases.","PeriodicalId":74651,"journal":{"name":"Receptors (Basel, Switzerland)","volume":"142 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87964233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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