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}
Pub Date : 2022-11-07DOI: 10.3390/receptors1010005
R. Coveñas, F. D. Rodríguez, M. Muñoz
The important role played by the substance P (SP)/neurokinin-1 receptor (NK-1R) system in cancer is reviewed: this includes tumor cell proliferation and migration, anti-apoptotic mechanisms, and angiogenesis. SP, through the NK-1R, behaves as a universal mitogen in cancer cells. The NK-1R is overexpressed in tumor cells and, in addition, affects the viability of cancer cells. NK-1R antagonists counteract all the previous actions mediated by SP through NK-1R. In a concentration-dependent manner, these antagonists promote tumor cell death by apoptosis. Therefore, NK-1R is a potential and promising therapeutic target for cancer treatment by using NK-1R antagonists (e.g., aprepitant) alone or in combination therapy with chemotherapy or radiotherapy.
{"title":"The Neurokinin-1 Receptor: A Promising Antitumor Target","authors":"R. Coveñas, F. D. Rodríguez, M. Muñoz","doi":"10.3390/receptors1010005","DOIUrl":"https://doi.org/10.3390/receptors1010005","url":null,"abstract":"The important role played by the substance P (SP)/neurokinin-1 receptor (NK-1R) system in cancer is reviewed: this includes tumor cell proliferation and migration, anti-apoptotic mechanisms, and angiogenesis. SP, through the NK-1R, behaves as a universal mitogen in cancer cells. The NK-1R is overexpressed in tumor cells and, in addition, affects the viability of cancer cells. NK-1R antagonists counteract all the previous actions mediated by SP through NK-1R. In a concentration-dependent manner, these antagonists promote tumor cell death by apoptosis. Therefore, NK-1R is a potential and promising therapeutic target for cancer treatment by using NK-1R antagonists (e.g., aprepitant) alone or in combination therapy with chemotherapy or radiotherapy.","PeriodicalId":74651,"journal":{"name":"Receptors (Basel, Switzerland)","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82219777","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 : 2022-10-08DOI: 10.3390/receptors1010004
F. D. Rodríguez, R. Coveñas
Substance P (SP), the first isolated neuropeptide, belongs to the family of tachykinin peptides and is the natural ligand of neurokinin-1 receptors (NK-1R), also named SP receptors. The undecapeptide activates the receptor after specifically binding to the protein and triggers intracellular signals leading to different biochemical events and subsequent physiological responses. This study reviews the main architectural features of this receptor, its interaction with natural and synthetic ligands, and the functional conformational states adopted after interacting with ligands and effector G proteins. The analysis of the main intracellular signaling pathways turned on by the activation of NK-1 receptors reveals the participation of different proteins supporting metabolic changes and genetic and epigenetic regulations. Furthermore, the analysis of receptor occupancy and receptor downregulation and internalization represents a complex and estimable field for basic and clinical research focused on the role of SP in physiopathology. Profound knowledge of the structural dynamics of NK-1R may help develop and assay new selective synthetic non-peptide antagonists as potential therapeutic agents applied to various pathologies and symptoms.
{"title":"The Neurokinin-1 Receptor: Structure Dynamics and Signaling","authors":"F. D. Rodríguez, R. Coveñas","doi":"10.3390/receptors1010004","DOIUrl":"https://doi.org/10.3390/receptors1010004","url":null,"abstract":"Substance P (SP), the first isolated neuropeptide, belongs to the family of tachykinin peptides and is the natural ligand of neurokinin-1 receptors (NK-1R), also named SP receptors. The undecapeptide activates the receptor after specifically binding to the protein and triggers intracellular signals leading to different biochemical events and subsequent physiological responses. This study reviews the main architectural features of this receptor, its interaction with natural and synthetic ligands, and the functional conformational states adopted after interacting with ligands and effector G proteins. The analysis of the main intracellular signaling pathways turned on by the activation of NK-1 receptors reveals the participation of different proteins supporting metabolic changes and genetic and epigenetic regulations. Furthermore, the analysis of receptor occupancy and receptor downregulation and internalization represents a complex and estimable field for basic and clinical research focused on the role of SP in physiopathology. Profound knowledge of the structural dynamics of NK-1R may help develop and assay new selective synthetic non-peptide antagonists as potential therapeutic agents applied to various pathologies and symptoms.","PeriodicalId":74651,"journal":{"name":"Receptors (Basel, Switzerland)","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91278010","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 : 2022-08-09DOI: 10.3390/receptors1010003
V. Tetz, G. Tetz
Here, our data provide the first evidence for the existence of a previously unknown receptive system formed by novel DNA- and RNA-based receptors in eukaryotes. This system, named the TR-system, is capable of recognizing and generating a response to different environmental factors and has been shown to orchestrate major vital functions of fungi, mammalian cells, and plants. Recently, we discovered the existence of a similar regulatory system in prokaryotes. These DNA- and RNA-based receptors are localized outside of the membrane forming a type of a network around cells that responds to a variety of chemical, biological, and physical factors and enabled the TR-system to regulate major aspects of eukaryotic cell life as follows: growth, including reproduction and development of multicellular structures; sensitivity to temperature, geomagnetic field, UV, light, and hormones; interaction with viruses; gene expression, recognition and utilization of nutrients. The TR-system was also implicated in cell-memory formation and was determined to be responsible for its maintenance and the forgetting of preceding events. This system is the most distant receptive and regulatory system of the cell that regulates interactions with the outer environment and governs the functions of other receptor-mediated signaling pathways.
{"title":"Novel Cell Receptor System of Eukaryotes Formed by Previously Unknown Nucleic Acid-Based Receptors","authors":"V. Tetz, G. Tetz","doi":"10.3390/receptors1010003","DOIUrl":"https://doi.org/10.3390/receptors1010003","url":null,"abstract":"Here, our data provide the first evidence for the existence of a previously unknown receptive system formed by novel DNA- and RNA-based receptors in eukaryotes. This system, named the TR-system, is capable of recognizing and generating a response to different environmental factors and has been shown to orchestrate major vital functions of fungi, mammalian cells, and plants. Recently, we discovered the existence of a similar regulatory system in prokaryotes. These DNA- and RNA-based receptors are localized outside of the membrane forming a type of a network around cells that responds to a variety of chemical, biological, and physical factors and enabled the TR-system to regulate major aspects of eukaryotic cell life as follows: growth, including reproduction and development of multicellular structures; sensitivity to temperature, geomagnetic field, UV, light, and hormones; interaction with viruses; gene expression, recognition and utilization of nutrients. The TR-system was also implicated in cell-memory formation and was determined to be responsible for its maintenance and the forgetting of preceding events. This system is the most distant receptive and regulatory system of the cell that regulates interactions with the outer environment and governs the functions of other receptor-mediated signaling pathways.","PeriodicalId":74651,"journal":{"name":"Receptors (Basel, Switzerland)","volume":"219 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76600247","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 : 2022-08-02DOI: 10.3390/receptors1010002
K. Walsh, A. E. Holmes
(1) Background: In addition to the major phytocannabinoids, trans-Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), the cannabis plant (Cannabis sativa L.) synthesizes over 120 additional cannabinoids that are known as minor cannabinoids. These minor cannabinoids have been proposed to act as agonists and antagonists at numerous targets including cannabinoid type 1 (CB1) and type 2 (CB2) receptors, transient receptor potential (TRP) channels and others. The goal of the present study was to determine the agonist effects of the minor cannabinoids: cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabitriol (CBT) and cannabidivarin (CBDV) at the CB1 receptor. In addition, the CB1 receptor antagonist effects of Δ9-tetrahydrocannabivarin (Δ9-THCV) were compared with its isomer Δ8-tetrahydrocannabivarin (Δ8-THCV). (2) Methods: CB1 receptor activity was monitored by measuring cannabinoid activation of G protein-gated inward rectifier K+ (GIRK) channels in AtT20 pituitary cells using a membrane potential-sensitive fluorescent dye assay. (3) Results: When compared to the CB1 receptor full agonist WIN 55,212-2 and the partial agonist Δ9-THC, none of the minor cannabinoids caused a significant activation of Gi/GIRK channel signaling. However, Δ9-THCV and Δ8-THCV antagonized the effect of WIN 55,212-2 with half-maximal inhibitory concentrations (IC50s) of 434 nM and 757 nM, respectively. Δ9-THCV antagonism of the CB1 receptor was “ligand-dependent”; Δ9-THCV was more potent in inhibiting WIN 55,212-2 and 2-arachidonoylglycerol (2-AG) than Δ9-THC. (4) Conclusions: While none of the minor cannabinoids caused Gi/GIRK channel activation, Δ9-THCV antagonized the CB1 receptor in an isomer- and ligand-dependent manner.
{"title":"Pharmacology of Minor Cannabinoids at the Cannabinoid CB1 Receptor: Isomer- and Ligand-Dependent Antagonism by Tetrahydrocannabivarin","authors":"K. Walsh, A. E. Holmes","doi":"10.3390/receptors1010002","DOIUrl":"https://doi.org/10.3390/receptors1010002","url":null,"abstract":"(1) Background: In addition to the major phytocannabinoids, trans-Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), the cannabis plant (Cannabis sativa L.) synthesizes over 120 additional cannabinoids that are known as minor cannabinoids. These minor cannabinoids have been proposed to act as agonists and antagonists at numerous targets including cannabinoid type 1 (CB1) and type 2 (CB2) receptors, transient receptor potential (TRP) channels and others. The goal of the present study was to determine the agonist effects of the minor cannabinoids: cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabitriol (CBT) and cannabidivarin (CBDV) at the CB1 receptor. In addition, the CB1 receptor antagonist effects of Δ9-tetrahydrocannabivarin (Δ9-THCV) were compared with its isomer Δ8-tetrahydrocannabivarin (Δ8-THCV). (2) Methods: CB1 receptor activity was monitored by measuring cannabinoid activation of G protein-gated inward rectifier K+ (GIRK) channels in AtT20 pituitary cells using a membrane potential-sensitive fluorescent dye assay. (3) Results: When compared to the CB1 receptor full agonist WIN 55,212-2 and the partial agonist Δ9-THC, none of the minor cannabinoids caused a significant activation of Gi/GIRK channel signaling. However, Δ9-THCV and Δ8-THCV antagonized the effect of WIN 55,212-2 with half-maximal inhibitory concentrations (IC50s) of 434 nM and 757 nM, respectively. Δ9-THCV antagonism of the CB1 receptor was “ligand-dependent”; Δ9-THCV was more potent in inhibiting WIN 55,212-2 and 2-arachidonoylglycerol (2-AG) than Δ9-THC. (4) Conclusions: While none of the minor cannabinoids caused Gi/GIRK channel activation, Δ9-THCV antagonized the CB1 receptor in an isomer- and ligand-dependent manner.","PeriodicalId":74651,"journal":{"name":"Receptors (Basel, Switzerland)","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88543336","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 : 2022-05-13DOI: 10.3390/receptors1010001
S. Safe
Receptors are widely expressed in human tissues and play a key role in maintaining cellular homeostasis and in pathophysiology, and they are important drug targets for the treatment of human diseases [...]
{"title":"Excited about Receptors","authors":"S. Safe","doi":"10.3390/receptors1010001","DOIUrl":"https://doi.org/10.3390/receptors1010001","url":null,"abstract":"Receptors are widely expressed in human tissues and play a key role in maintaining cellular homeostasis and in pathophysiology, and they are important drug targets for the treatment of human diseases [...]","PeriodicalId":74651,"journal":{"name":"Receptors (Basel, Switzerland)","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87003380","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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