Pharmacological Reviews最新文献

{"title":"Generation of Comprehensive GPCR-Transducer-Deficient Cell Lines to Dissect the Complexity of GPCR Signaling.","authors":"Ayaki Saito, Ryoji Kise, Asuka Inoue","doi":"10.1124/pharmrev.124.001186","DOIUrl":"10.1124/pharmrev.124.001186","url":null,"abstract":"<p><p>G-protein-coupled receptors (GPCRs) compose the largest family of transmembrane receptors and are targets of approximately one-third of Food and Drug Administration-approved drugs owing to their involvement in almost all physiologic processes. GPCR signaling occurs through the activation of heterotrimeric G-protein complexes and <i>β</i>-arrestins, both of which serve as transducers, resulting in distinct cellular responses. Despite seeming simple at first glance, accumulating evidence indicates that activation of either transducer is not a straightforward process as a stimulation of a single molecule has the potential to activate multiple signaling branches. The complexity of GPCR signaling arises from the aspects of G-protein-coupling selectivity, biased signaling, interpathway crosstalk, and variable molecular modifications generating these diverse signaling patterns. Numerous questions relative to these aspects of signaling remained unanswered until the recent development of CRISPR genome-editing technology. Such genome editing technology presents opportunities to chronically eliminate the expression of G-protein subunits, <i>β</i>-arrestins, G-protein-coupled receptor kinases (GRKs), and many other signaling nodes in the GPCR pathways at one's convenience. Here, we review the practicality of using CRISPR-derived knockout (KO) cells in the experimental contexts of unraveling the molecular details of GPCR signaling mechanisms. To mention a few, KO cells have revealed the contribution of <i>β</i>-arrestins in ERK activation, G<i>α</i> protein selectivity, GRK-based regulation of GPCRs, and many more, hence validating its broad applicability in GPCR studies. SIGNIFICANCE STATEMENT: This review emphasizes the practical application of G-protein-coupled receptor (GPCR) transducer knockout (KO) cells in dissecting the intricate regulatory mechanisms of the GPCR signaling network. Currently available cell lines, along with accumulating KO cell lines in diverse cell types, offer valuable resources for systematically elucidating GPCR signaling regulation. Given the association of GPCR signaling with numerous diseases, uncovering the system-based signaling map is crucial for advancing the development of novel drugs targeting specific diseases.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":" ","pages":"599-619"},"PeriodicalIF":21.1,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140892136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel and Emerging Treatments to Target Pathophysiological Mechanisms in Various Phenotypes of Multiple Sclerosis.","authors":"Gabriel Bsteh, Assunta Dal Bianco, Tobias Zrzavy, Thomas Berger","doi":"10.1124/pharmrev.124.001073","DOIUrl":"10.1124/pharmrev.124.001073","url":null,"abstract":"<p><p>The objective is to comprehensively review novel pharmacotherapies used in multiple sclerosis (MS) and the possibilities they may carry for therapeutic improvement. Specifically, we discuss pathophysiological mechanisms worth targeting in MS, ranging from well known targets, such as autoinflammation and demyelination, to more novel and advanced targets, such as neuroaxonal damage and repair. To set the stage, a brief overview of clinical MS phenotypes is provided, followed by a comprehensive recapitulation of both clinical and paraclinical outcomes available to assess the effectiveness of treatments in achieving these targets. Finally, we discuss various promising novel and emerging treatments, including their respective hypothesized modes of action and currently available evidence from clinical trials. SIGNIFICANCE STATEMENT: This comprehensive review discusses pathophysiological mechanisms worth targeting in multiple sclerosis. Various promising novel and emerging treatments, including their respective hypothesized modes of action and currently available evidence from clinical trials, are reviewed.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":" ","pages":"564-578"},"PeriodicalIF":21.1,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140892139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacology and Precision Medicine-Preparing for the Next Era in Clinical Medicine-Editorial.","authors":"Rhian M Touyz","doi":"10.1124/pharmrev.124.001017","DOIUrl":"https://doi.org/10.1124/pharmrev.124.001017","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"76 4","pages":"559-560"},"PeriodicalIF":21.1,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141321267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Chance to Grow and Excel as an Associate Editor of <i>Pharmacological Reviews</i>-Editorial.","authors":"Ali H Eid","doi":"10.1124/pharmrev.124.001101","DOIUrl":"https://doi.org/10.1124/pharmrev.124.001101","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"76 3","pages":"321-322"},"PeriodicalIF":21.1,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140857629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A 25-Year Journey as Author and Associate Editor of <i>Pharmacological Reviews</i>-Editorial.","authors":"Martin C Michel","doi":"10.1124/pharmrev.123.000990","DOIUrl":"10.1124/pharmrev.123.000990","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"76 2","pages":"196-198"},"PeriodicalIF":21.1,"publicationDate":"2024-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139730223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of G Protein-Coupled Receptors and Receptor Kinases in Pancreatic <i>β</i>-Cell Function and Diabetes.","authors":"Matthew J Varney, Jeffrey L Benovic","doi":"10.1124/pharmrev.123.001015","DOIUrl":"10.1124/pharmrev.123.001015","url":null,"abstract":"<p><p>Type 2 diabetes (T2D) mellitus has emerged as a major global health concern that has accelerated in recent years due to poor diet and lifestyle. Afflicted individuals have high blood glucose levels that stem from the inability of the pancreas to make enough insulin to meet demand. Although medication can help to maintain normal blood glucose levels in individuals with chronic disease, many of these medicines are outdated, have severe side effects, and often become less efficacious over time, necessitating the need for insulin therapy. G protein-coupled receptors (GPCRs) regulate many physiologic processes, including blood glucose levels. In pancreatic <i>β</i> cells, GPCRs regulate <i>β</i>-cell growth, apoptosis, and insulin secretion, which are all critical in maintaining sufficient <i>β</i>-cell mass and insulin output to ensure euglycemia. In recent years, new insights into the signaling of incretin receptors and other GPCRs have underscored the potential of these receptors as desirable targets in the treatment of diabetes. The signaling of these receptors is modulated by GPCR kinases (GRKs) that phosphorylate agonist-activated GPCRs, marking the receptor for arrestin binding and internalization. Interestingly, genome-wide association studies using diabetic patient cohorts link the GRKs and arrestins with T2D. Moreover, recent reports show that GRKs and arrestins expressed in the <i>β</i> cell serve a critical role in the regulation of <i>β</i>-cell function, including <i>β</i>-cell growth and insulin secretion in both GPCR-dependent and -independent pathways. In this review, we describe recent insights into GPCR signaling and the importance of GRK function in modulating <i>β</i>-cell physiology. SIGNIFICANCE STATEMENT: Pancreatic <i>β</i> cells contain a diverse array of G protein-coupled receptors (GPCRs) that have been shown to improve <i>β</i>-cell function and survival, yet only a handful have been successfully targeted in the treatment of diabetes. This review discusses recent advances in our understanding of <i>β</i>-cell GPCR pharmacology and regulation by GPCR kinases while also highlighting the necessity of investigating islet-enriched GPCRs that have largely been unexplored to unveil novel treatment strategies.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"76 2","pages":"267-299"},"PeriodicalIF":21.1,"publicationDate":"2024-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10877731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139730224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological Reviews’75th Year Anniversary: Past and Future—Editorial","authors":"Lynette C. Daws","doi":"10.1124/pharmrev.123.000989","DOIUrl":"https://doi.org/10.1124/pharmrev.123.000989","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"1 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138657374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emergence of extracellular vesicles as 'liquid biopsy' for neurological disorders: Boom or Bust","authors":"Ashish Kumar, Michael A. Nader, Gagan Deep","doi":"10.1124/pharmrev.122.000788","DOIUrl":"https://doi.org/10.1124/pharmrev.122.000788","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":" 0","pages":""},"PeriodicalIF":21.1,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138961718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of Pain Perception by Microbiota in Parkinson Disease.","authors":"Zulmary Manjarres, Margarita Calvo, Rodrigo Pacheco","doi":"10.1124/pharmrev.122.000674","DOIUrl":"10.1124/pharmrev.122.000674","url":null,"abstract":"<p><p>Pain perception involves current stimulation in peripheral nociceptive nerves and the subsequent stimulation of postsynaptic excitatory neurons in the spinal cord. Importantly, in chronic pain, the neural activity of both peripheral nociceptors and postsynaptic neurons in the central nervous system is influenced by several inflammatory mediators produced by the immune system. Growing evidence has indicated that the commensal microbiota plays an active role in regulating pain perception by either acting directly on nociceptors or indirectly through the modulation of the inflammatory activity on immune cells. This symbiotic relationship is mediated by soluble bacterial mediators or intrinsic structural components of bacteria that act on eukaryotic cells, including neurons, microglia, astrocytes, macrophages, T cells, enterochromaffin cells, and enteric glial cells. The molecular mechanisms involve bacterial molecules that act directly on neurons, affecting their excitability, or indirectly on non-neuronal cells, inducing changes in the production of proinflammatory or anti-inflammatory mediators. Importantly, Parkinson disease, a neurodegenerative and inflammatory disorder that affects mainly the dopaminergic neurons implicated in the control of voluntary movements, involves not only a motor decline but also nonmotor symptomatology, including chronic pain. Of note, several recent studies have shown that Parkinson disease involves a dysbiosis in the composition of the gut microbiota. In this review, we first summarize, integrate, and classify the molecular mechanisms implicated in the microbiota-mediated regulation of chronic pain. Second, we analyze the changes on the commensal microbiota associated to Parkinson disease and propose how these changes affect the development of chronic pain in this pathology. SIGNIFICANCE STATEMENT: The microbiota regulates chronic pain through the action of bacterial signals into two main locations: the peripheral nociceptors and the postsynaptic excitatory neurons in the spinal cord. The dysbiosis associated to Parkinson disease reveals increased representation of commensals that potentially exacerbate chronic pain and reduced levels of bacteria with beneficial effects on pain. This review encourages further research to better understand the signals involved in bacteria-bacteria and bacteria-host communication to get the clues for the development of probiotics with therapeutic potential.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":" ","pages":"7-36"},"PeriodicalIF":21.1,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49680807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Halogenated Antimicrobial Agents to Combat Drug-Resistant Pathogens.","authors":"Olajide Sunday Faleye, Bharath Reddy Boya, Jin-Hyung Lee, Inho Choi, Jintae Lee","doi":"10.1124/pharmrev.123.000863","DOIUrl":"10.1124/pharmrev.123.000863","url":null,"abstract":"<p><p>Antimicrobial resistance presents us with a potential global crisis as it undermines the abilities of conventional antibiotics to combat pathogenic microbes. The history of antimicrobial agents is replete with examples of scaffolds containing halogens. In this review, we discuss the impacts of halogen atoms in various antibiotic types and antimicrobial scaffolds and their modes of action, structure-activity relationships, and the contributions of halogen atoms in antimicrobial activity and drug resistance. Other halogenated molecules, including carbohydrates, peptides, lipids, and polymeric complexes, are also reviewed, and the effects of halogenated scaffolds on pharmacokinetics, pharmacodynamics, and factors affecting antimicrobial and antivirulence activities are presented. Furthermore, the potential of halogenation to circumvent antimicrobial resistance and rejuvenate impotent antibiotics is addressed. This review provides an overview of the significance of halogenation, the abilities of halogens to interact in biomolecular settings and enhance pharmacological properties, and their potential therapeutic usages in preventing a postantibiotic era. SIGNIFICANCE STATEMENT: Antimicrobial resistance and the increasing impotence of antibiotics are critical threats to global health. The roles and importance of halogen atoms in antimicrobial drug scaffolds have been established, but comparatively little is known of their pharmacological impacts on drug resistance and antivirulence activities. This review is the first to extensively evaluate the roles of halogen atoms in various antibiotic classes and pharmacological scaffolds and to provide an overview of their ability to overcome antimicrobial resistance.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":" ","pages":"90-141"},"PeriodicalIF":21.1,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41237451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}