Molecular Pharmacology最新文献

{"title":"FANNING THE FLAMES OF ER STRESS:Can sphingolipid metabolism be targeted to enhance ER stress associated immunogenic cell death in cancer?","authors":"J. Hengst, Asvelt J. Nduwumwami, Arati Sharma, Jong K. Yun","doi":"10.1124/molpharm.123.000786","DOIUrl":"https://doi.org/10.1124/molpharm.123.000786","url":null,"abstract":"","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"25 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138951133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"St. John's Wort Formulations Induce Rat CYP3A23-3A1 Independent of Their Hyperforin Content.","authors":"Anima M Schäfer, Marta A Rysz, Julia Schädeli, Michelle Hübscher, Haleh Khosravi, Michelle Fehr, Isabell Seibert, Olivier Potterat, Martin Smieško, Henriette E Meyer Zu Schwabedissen","doi":"10.1124/molpharm.123.000725","DOIUrl":"10.1124/molpharm.123.000725","url":null,"abstract":"<p><p>The pregnane X receptor (PXR) is a ligand-activated regulator of cytochrome P450 (CYP)3A enzymes. Among the ligands of human PXR is hyperforin, a constituent of St John's wort (SJW) extracts and potent inducer of human CYP3A4. It was the aim of this study to compare the effect of hyperforin and SJW formulations controlled for its content on CYP3A23-3A1 in rats. Hyperiplant was used as it contains a high hyperforin content and Rebalance because it is controlled for a low hyperforin content. In silico analysis revealed a weak hyperforin-rPXR binding affinity, which was further supported in cell-based reporter gene assays showing no hyperforin-mediated reporter activation in presence of rPXR. However, cellular exposure to Hyperiplant and Rebalance transactivated the CYP3A reporter 3.8-fold and 2.8-fold, respectively, and they induced <i>Cyp3a23-3a1</i> mRNA expression in rat hepatoma cells compared with control 48-fold and 18-fold, respectively. In Wistar rats treated for 10 days with 400 mg/kg of Hyperiplant, we observed 1.8 times the <i>Cyp3a23-3a1</i> mRNA expression, a 2.6-fold higher CYP3A23-3A1 protein amount, and a 1.6-fold increase in activity compared with controls. For Rebalance we only observed a 1.8-fold hepatic increase of CYP3A23-3A1 protein compared with control animals. Even though there are differing effects on r<i>Cyp3a23-3a1</i>/CYP3A23-3A1 in rat liver reflecting the hyperforin content of the SJW extracts, the modulation is most likely not linked to an interaction of hyperforin with rPXR. SIGNIFICANCE STATEMENT: Treatment with St John's wort (SJW) has been reported to affect CYP3A expression and activity in rats. Our comparative study further supports this finding but shows that the pregnane X receptor-ligand hyperforin is not the driving force for changes in rat CYP3A23-3A1 expression and function in vivo and in vitro. Importantly, CYP3A induction mimics findings in humans, but our results suggest that another so far unknown constituent of SJW is responsible for the expression- and function-modifying effects in rat liver.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":" ","pages":"14-22"},"PeriodicalIF":3.2,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49679746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Passive Immunotherapies Targeting Amyloid-<i>β</i> in Alzheimer's Disease: A Quantitative Systems Pharmacology Perspective.","authors":"Milica Marković, Jelica Milošević, Weirong Wang, Yanguang Cao","doi":"10.1124/molpharm.123.000726","DOIUrl":"10.1124/molpharm.123.000726","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-<i>β</i> (A<i>β</i>) protein accumulation in the brain. Passive immunotherapies using monoclonal antibodies for targeting A<i>β</i> have shown promise for AD treatment. Indeed, recent US Food and Drug Administration approval of aducanumab and lecanemab, alongside positive donanemab Phase III results demonstrated clinical efficacy after decades of failed clinical trials for AD. However, the pharmacological basis distinguishing clinically effective from ineffective therapies remains unclear, impeding development of potent therapeutics. This study aimed to provide a quantitative perspective for effectively targeting A<i>β</i> with antibodies. We first reviewed the contradicting results associated with the amyloid hypothesis and the pharmacological basis of A<i>β</i> immunotherapy. Subsequently, we developed a quantitative systems pharmacology (QSP) model that describes the non-linear progression of A<i>β</i> pathology and the pharmacologic actions of the A<i>β</i>-targeting antibodies. Using the QSP model, we analyzed various scenarios for effective passive immunotherapy for AD. The model revealed that binding exclusively to the A<i>β</i> monomer has minimal effect on A<i>β</i> aggregation and plaque reduction, making the antibody affinity toward A<i>β</i> monomer unwanted, as it could become a distractive mechanism for plaque reduction. Neither early intervention, high brain penetration, nor increased dose could yield significant improvement of clinical efficacy for antibodies targeting solely monomers. Antibodies that bind all A<i>β</i> species but lack effector function exhibited moderate effects in plaque reduction. Our model highlights the importance of binding aggregate A<i>β</i> species and incorporating effector functions for efficient and early plaque reduction, guiding the development of more effective therapies for this devastating disease. SIGNIFICANCE STATEMENT: Despite previous unsuccessful attempts spanning several decades, passive immunotherapies utilizing monoclonal antibodies for targeting amyloid-beta (A<i>β</i>) have demonstrated promise with two recent FDA approvals. However, the pharmacological basis that differentiates clinically effective therapies from ineffective ones remains elusive. Our study offers a quantitative systems pharmacology perspective, emphasizing the significance of selectively targeting specific A<i>β</i> species and importance of antibody effector functions. This perspective sheds light on the development of more effective therapies for this devastating disease.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":" ","pages":"1-13"},"PeriodicalIF":3.2,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71425098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synergy between Interleukin-1<i>β</i>, Interferon-<i>γ</i>, and Glucocorticoids to Induce TLR2 Expression Involves NF-<i>κ</i>B, STAT1, and the Glucocorticoid Receptor.","authors":"Akanksha Bansal, Cora Kooi, Keerthana Kalyanaraman, Sachman Gill, Andrew Thorne, Priyanka Chandramohan, Amandah Necker-Brown, Mahmoud M Mostafa, Arya Milani, Richard Leigh, Robert Newton","doi":"10.1124/molpharm.123.000740","DOIUrl":"10.1124/molpharm.123.000740","url":null,"abstract":"<p><p>Glucocorticoids act via the glucocorticoid receptor (GR; NR3C1) to downregulate inflammatory gene expression and are effective treatments for mild to moderate asthma. However, in severe asthma and virus-induced exacerbations, glucocorticoid therapies are less efficacious, possibly due to reduced repressive ability and/or the increased expression of proinflammatory genes. In human A549 epithelial and primary human bronchial epithelial cells, toll-like receptor (TLR)-2 mRNA and protein were <i>supra</i>-additively induced by interleukin-1<i>β</i> (IL-1<i>β</i>) plus dexamethasone (IL-1<i>β</i>+Dex), interferon-<i>γ</i> (IFN-<i>γ</i>) plus dexamethasone (IFN-<i>γ</i>+Dex), and IL-1<i>β</i> plus IFN-<i>γ</i> plus dexamethasone (IL-1<i>β</i>+IFN-<i>γ</i>+Dex). Indeed, ∼34- to 2100-fold increases were apparent at 24 hours for IL-1<i>β</i>+IFN-<i>γ</i>+Dex, and this was greater than for any single or dual treatment. Using the A549 cell model, TLR2 induction by IL-1<i>β</i>+IFN-<i>γ</i>+Dex was antagonized by Org34517, a competitive GR antagonist. Further, when combined with IL-1<i>β</i>, IFN-<i>γ</i>, or IL-1<i>β</i>+IFN-<i>γ</i>, the enhancements by dexamethasone on TLR2 expression required GR. Likewise, inhibitor of <i>κ</i>B kinase 2 inhibitors reduced IL-1<i>β</i>+IFN-<i>γ</i>+Dex-induced TLR2 expression, and TLR2 expression induced by IL-1<i>β</i>+Dex, with or without IFN-<i>γ</i>, required the nuclear factor (NF)-<i>κ</i>B subunit, p65. Similarly, signal transducer and activator of transcription (STAT)-1 phosphorylation and <i>γ</i>-interferon-activated sequence-dependent transcription were induced by IFN-<i>γ</i> These, along with IL-1<i>β</i>+IFN-<i>γ</i>+Dex-induced TLR2 expression, were inhibited by Janus kinase (JAK) inhibitors. As IL-1<i>β</i>+IFN-<i>γ</i>+Dex-induced TLR2 expression also required STAT1, this study reveals cooperation between JAK-STAT1, NF-<i>κ</i>B, and GR to upregulate TLR2 expression. Since TLR2 agonism elicits inflammatory responses, we propose that synergies involving TLR2 may occur within the cytokine milieu present in the immunopathology of glucocorticoid-resistant disease, and this could promote glucocorticoid resistance. SIGNIFICANCE STATEMENT: This study highlights that in human pulmonary epithelial cells, glucocorticoids, when combined with the inflammatory cytokines interleukin-1<i>β</i> (IL-1<i>β</i>) and interferon-<i>γ</i> (IFN-<i>γ</i>), can synergistically induce the expression of inflammatory genes, such as TLR2. This effect involved positive combinatorial interactions between NF-<i>κ</i>B/p65, glucocorticoid receptor, and JAK-STAT1 signaling to synergistically upregulate TLR2 expression. Thus, synergies involving glucocorticoid enhancement of TLR2 expression may occur in the immunopathology of glucocorticoid-resistant inflammatory diseases, including severe asthma.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":" ","pages":"23-38"},"PeriodicalIF":3.2,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49679747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual-Activity Fluoroquinolone-Transportan 10 Conjugates Offer Alternative Leukemia Therapy during Hematopoietic Cell Transplantation.","authors":"Jan Jakub Lica, Mateusz Heldt, Milosz Wieczór, Pawel Chodnicki, Natalia Ptaszyńska, Natalia Maciejewska, Anna Łęgowska, Wioletta Brankiewicz, Katarzyna Gucwa, Anna Stupak, Bhaskar Pradhan, Agata Gitlin-Domagalska, Dawid Dębowski, Sławomir Milewski, Maria Bieniaszewska, Grzegorz Jan Grabe, Andrzej Hellmann, Krzysztof Rolka","doi":"10.1124/molpharm.123.000735","DOIUrl":"10.1124/molpharm.123.000735","url":null,"abstract":"<p><p>Hematopoietic cell transplantation (HCT) is often considered a last resort leukemia treatment, fraught with limited success due to microbial infections, a leading cause of mortality in leukemia patients. To address this critical issue, we explored a novel approach by synthesizing antileukemic agents containing antibacterial substances. This innovative strategy involves conjugating fluoroquinolone antibiotics, such as ciprofloxacin (CIP) or levofloxacin (LVX), with the cell-penetrating peptide transportan 10 (TP10). Here, we demonstrate that the resultant compounds display promising biologic activities in preclinical studies. These novel conjugates not only exhibit potent antimicrobial effects but are also selective against leukemia cells. The cytotoxic mechanism involves rapid disruption of cell membrane asymmetry leading to membrane damage. Importantly, these conjugates penetrated mammalian cells, accumulating within the nuclear membrane without significant effect on cellular architecture or mitochondrial function. Molecular simulations elucidated the aggregation tendencies of TP10 conjugates within lipid bilayers, resulting in membrane disruption and permeabilization. Moreover, mass spectrometry analysis confirmed efficient reduction of disulfide bonds within TP10 conjugates, facilitating release and activation of the fluoroquinolone derivatives. Intriguingly, these compounds inhibited human topoisomerases, setting them apart from traditional fluoroquinolones. Remarkably, TP10 conjugates generated lower intracellular levels of reactive oxygen species compared with CIP and LVX. The combination of antibacterial and antileukemic properties, coupled with selective cytostatic effects and minimal toxicity toward healthy cells, positions TP10 derivatives as promising candidates for innovative therapeutic approaches in the context of antileukemic HCT. This study highlights their potential in search of more effective leukemia treatments. SIGNIFICANCE STATEMENT: Fluoroquinolones are commonly used antibiotics, while transportan 10 (TP10) is a cell-penetrating peptide (CPP) with anticancer properties. In HCT, microbial infections are the primary cause of illness and death. Combining TP10 with fluoroquinolones enhanced their effects on different cell types. The dual pharmacological action of these conjugates offers a promising proof-of-concept solution for leukemic patients undergoing HCT. Strategically designed therapeutics, incorporating CPPs with antibacterial properties, have the potential to reduce microbial infections in the treatment of malignancies.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":" ","pages":"39-53"},"PeriodicalIF":3.2,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136398236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to \"Gossypetin Prevents the Progression of Nonalcoholic Steatohepatitis by Regulating Oxidative Stress and AMP-Activated Protein Kinase\".","authors":"","doi":"10.1124/molpharm.123.000675err","DOIUrl":"10.1124/molpharm.123.000675err","url":null,"abstract":"","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"105 1","pages":"63"},"PeriodicalIF":3.2,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138807372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A ¹⁹F-qNMR-Guided Mathematical Model for G Protein-Coupled Receptor Signaling.","authors":"Jesús Giraldo, Jesper J Madsen, Xudong Wang, Lei Wang, Cheng Zhang, Libin Ye","doi":"10.1124/molpharm.123.000754","DOIUrl":"10.1124/molpharm.123.000754","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) exhibit a wide range of pharmacological efficacies, yet the molecular mechanisms responsible for the differential efficacies in response to various ligands remain poorly understood. This lack of understanding has hindered the development of a solid foundation for establishing a mathematical model for signaling efficacy. However, recent progress has been made in delineating and quantifying receptor conformational states and associating function with these conformations. This progress has allowed us to construct a mathematical model for GPCR signaling efficacy that goes beyond the traditional ON/OFF binary switch model. In this study, we present a quantitative conformation-based mathematical model for GPCR signaling efficacy using the adenosine A_2A receptor (A_2AR) as a model system, under the guide of ¹⁹F quantitative nuclear magnetic resonance experiments. This model encompasses two signaling states, a fully activated state and a partially activated state, defined as being able to regulate the cognate G<i>α</i> _s nucleotide exchange with respective G protein recognition capacity. By quantifying the population distribution of each state, we can now in turn examine GPCR signaling efficacy. This advance provides a foundation for assessing GPCR signaling efficacy using a conformation-based mathematical model in response to ligand binding. SIGNIFICANCE STATEMENT: Mathematical models to describe signaling efficacy of GPCRs mostly suffer from considering only two states (ON/OFF). However, research indicates that a GPCR possesses multiple active-(like) states that can interact with Gαβγ independently, regulating varied nucleotide exchanges. With the guide of ¹⁹F-qNMR, the transitions among these states are quantified as a function of ligand and Gαβγ, serving as a foundation for a novel conformation-based mathematical signaling model.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":" ","pages":"54-62"},"PeriodicalIF":3.2,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10739436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71425097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug targeting of acyltransferases in the Triacylglyceride and 1-O-AcylCeramide biosynthetic pathways","authors":"Maria Hernandez-Corbacho, Daniel Canals","doi":"10.1124/molpharm.123.000763","DOIUrl":"https://doi.org/10.1124/molpharm.123.000763","url":null,"abstract":"Acyltransferase enzymes (EC 2.3.) are a large group of enzymes that transfer acyl groups to a large variety of substrates. This review focuses on fatty acyltransferases involved in the biosynthetic pathways of glycerolipids and sphingolipids and how these enzymes have been pharmacologically targeted in their biological context. Glycerolipids and sphingolipids, commonly treated independently in their regulation and biological functions, are put together to emphasize the parallelism in their metabolism and bioactive roles. Furthermore, a newly considered signaling molecule, 1-O-acylceramide, resulting from the acylation of ceramide by DGAT2 enzyme, is discussed. Finally, the implications of DGAT2 as a putative Ceramide AcylTransferase (CAT) enzyme, with a putative dual role in TAG and 1-O-acylceramide generation, are explored.","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"296 1 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138689688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression of ceramide synthases in mice and their roles in regulating acyl-chain sphingolipids: A framework for baseline levels and future implications in aging and disease","authors":"Whitney J. Richardson, Sophia B. Humphrey, Sophia M. Sears, Nicholas A. Hoffman, Andrew J. Orwick, Mark A. Doll, Chelsea L Doll, Catherine Xia, Maria Hernandez-Corbacho, Justin M. Snider, Lina M. Obeid, Yusuf A. Hannun, Ashley J. Snider, Leah J. Siskind","doi":"10.1124/molpharm.123.000788","DOIUrl":"https://doi.org/10.1124/molpharm.123.000788","url":null,"abstract":"Sphingolipids are an important class of lipids present in all eukaryotic cells that regulate critical cellular processes. Disturbances in sphingolipid homeostasis have been linked to several diseases in humans. Ceramides are central in sphingolipid metabolism and are largely synthesized by six ceramide synthase isoforms (CerS1-6), each with a preference for different fatty acyl chain lengths. While the tissue distribution of CerS mRNA expression in humans and the roles of CerS isoforms in synthesizing ceramides with different acyl chain lengths are known, it is unknown how CerS expression dictates ceramides and downstream metabolites within tissues. In this study, we analyzed sphingolipid levels and CerS mRNA expression in 3-month-old C57BL/6J mouse brain, heart, kidney, liver, lung, and skeletal muscle. The results showed that CerS expression and sphingolipid species abundance varied by tissue and that CerS expression was a predictor of ceramide species within tissues. Interestingly, though CerS expression was not predictive of complex sphingolipid species within all tissues, composite scores for CerSs contributions to total sphingolipids measured in each tissue correlated to CerS expression. Lastly, we determined that the most abundant ceramide species in mouse tissues aligned with CerS mRNA expression in corresponding human tissues (based on chain length preference), suggesting mice are relevant preclinical models for ceramide and sphingolipid research.","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"25 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138689971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Signaling specificity and kinetics of the human metabotropic glutamate receptors","authors":"Tyler W McCullock, Loren P Cardani, Paul J Kammermeier","doi":"10.1124/molpharm.123.000795","DOIUrl":"https://doi.org/10.1124/molpharm.123.000795","url":null,"abstract":"Metabotropic glutamate receptors (mGluRs) are obligate dimer G protein coupled receptors that can all function as homodimers. Here, each mGluR homodimer was examined for its G protein coupling profile using a BRET based assay that detects the interaction between a split YFP-tagged Gβ₁ᵯE;₂ and a Nanoluciferase tagged free GβᵯE; sensor, MAS-GRK3-ct-NLuc with 14 specific G⍺ proteins heterologously expressed, representing each family. Canonically, the group II and III mGluRs (2&amp;3, and 4, 6, 7&amp;8, respectively) are thought to couple to G_i/o exclusively. In addition, the group I mGluRs (1&amp;5) are known to couple to the G_q/11family, and generally thought to also couple to the PTX-sensitive G_i/o family; some reports have suggested G_scoupling is possible as cAMP elevations have been noted. In this study, coupling was observed with all 8 mGluRs through the G_i/o proteins, and only mGluR1&amp;5 through G_q/11, and perhaps surprisingly, not G₁₄. None activated any G_s protein. Interestingly, coupling was seen with the group I and II, but not the group III mGluRs to G₁₆. Slow but significant coupling to G_z was also seen with the group II receptors.","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"168 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2023-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138562095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}