Malgorzata Wasinska-Kalwa, Anahid Omran, Leonard Mach, Lucia Scipioni, Jara Bouma, Xiaoting Li, Silke Radetzki, Yelena Mostinski, Maria Schippers, Thais Gazzi, Cas van der Horst, Benjamin Brennecke, Annaleah Hanske, Yuliya Kolomeets, W Guba, David Sykes, Jens Peter von Kries, Johannes Broichhagen, Tian Hua, Dmitry Veprintsev, Laura H. Heitman, Sergio Oddi, Mauro Maccarrone, Uwe Grether, Marc Nazare
{"title":"Visualization of membrane localization and functional state of CB2R pools by matched agonist and inverse agonist probe pairs","authors":"Malgorzata Wasinska-Kalwa, Anahid Omran, Leonard Mach, Lucia Scipioni, Jara Bouma, Xiaoting Li, Silke Radetzki, Yelena Mostinski, Maria Schippers, Thais Gazzi, Cas van der Horst, Benjamin Brennecke, Annaleah Hanske, Yuliya Kolomeets, W Guba, David Sykes, Jens Peter von Kries, Johannes Broichhagen, Tian Hua, Dmitry Veprintsev, Laura H. Heitman, Sergio Oddi, Mauro Maccarrone, Uwe Grether, Marc Nazare","doi":"10.1039/d4sc00402g","DOIUrl":null,"url":null,"abstract":"The diversity of physiological roles of the endocannabinoid system has turned it into an attractive yet elusive therapeutic target. However, chemical probes with various functionalities could pave the way for a better understanding of the endocannabinoid system at the cellular level. Notably, inverse agonists of CB2R – a key receptor of the endocannabinoid system - lagged behind despite the evidence regarding the therapeutic potential of its antagonism. Herein, we report a matched fluorescent probe pair based on a common chemotype to address and visualize both the active and inactive states of CB2R, selectively. Alongside with extensive cross-validation by flow cytometry and confocal microscopy, we successfully visualize the intracellular localization of CB2R pools in live cells. The synthetic simplicity together with the high CB2R-selectivity and specificity of our probes, turn them into valuable tools in chemical biology and drug development that can benefit the clinical translatability of CB2R-based drugs.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":null,"pages":null},"PeriodicalIF":7.6000,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemical Science","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1039/d4sc00402g","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
Abstract
The diversity of physiological roles of the endocannabinoid system has turned it into an attractive yet elusive therapeutic target. However, chemical probes with various functionalities could pave the way for a better understanding of the endocannabinoid system at the cellular level. Notably, inverse agonists of CB2R – a key receptor of the endocannabinoid system - lagged behind despite the evidence regarding the therapeutic potential of its antagonism. Herein, we report a matched fluorescent probe pair based on a common chemotype to address and visualize both the active and inactive states of CB2R, selectively. Alongside with extensive cross-validation by flow cytometry and confocal microscopy, we successfully visualize the intracellular localization of CB2R pools in live cells. The synthetic simplicity together with the high CB2R-selectivity and specificity of our probes, turn them into valuable tools in chemical biology and drug development that can benefit the clinical translatability of CB2R-based drugs.
期刊介绍:
Chemical Science is a journal that encompasses various disciplines within the chemical sciences. Its scope includes publishing ground-breaking research with significant implications for its respective field, as well as appealing to a wider audience in related areas. To be considered for publication, articles must showcase innovative and original advances in their field of study and be presented in a manner that is understandable to scientists from diverse backgrounds. However, the journal generally does not publish highly specialized research.