{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T06:02:45Z","timestamp":1780293765736,"version":"3.54.0"},"reference-count":213,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>G protein-coupled receptors (GPCRs) are major drug targets for neurodegenerative, neurodevelopmental and psychiatric disorders and are targeted by a multitude of marketed drugs. Typically, multiple GPCRs are involved in diseases of this type, making precise modulation of these receptors crucial for beneficial responses in patients. In addition, the regulation of GPCRs by ligands and the concomitant modulation of physiological signaling pathways are highly fine-tuned. Considering these complex roles, the molecular understanding of GPCR biology has advanced considerably in recent years for these disorders. Likewise, recent developments in multiplexed cell-based assays that measure GPCR activities and downstream effects have substantially expanded the tools available for early drug discovery. In this review, we highlight the impact of GPCRs on these complex neurological disorders and review the current state of multiplexed, barcoded assays that can be used to screen for and validate GPCR-modulating compounds in living cells. These multiplexed assays enable rigorous assessment of drug selectivity across on- and off-target profiles, including within closely related GPCR subfamilies, while simultaneously capturing relevant systemic pathway responses. We therefore propose that the widespread use of this technology has the potential to substantially accelerate and de-risk GPCR-targeted drug development.<\/jats:p>","DOI":"10.3389\/fnmol.2026.1789400","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T05:28:40Z","timestamp":1780291720000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Decoding GPCR signaling in living cells to advance early therapeutic discovery for neurological disorders"],"prefix":"10.3389","volume":"19","author":[{"given":"Giulia","family":"Palladino","sequence":"first","affiliation":[{"name":"Systasy Bioscience GmbH","place":["Planegg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Patarra","sequence":"additional","affiliation":[{"name":"Systasy Bioscience GmbH","place":["Planegg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenke","family":"Li","sequence":"additional","affiliation":[{"name":"Research Group Cell Signalling, Department of Psychiatry and Psychotherapy, LMU University Hospital, LMU Munich","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moritz J.","family":"Rossner","sequence":"additional","affiliation":[{"name":"Systasy Bioscience GmbH","place":["Planegg, Germany"]},{"name":"Section of Molecular Neurobiology, Department of Psychiatry and Psychotherapy, LMU University Hospital, LMU Munich","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael C.","family":"Wehr","sequence":"additional","affiliation":[{"name":"Systasy Bioscience GmbH","place":["Planegg, Germany"]},{"name":"Research Group Cell Signalling, Department of Psychiatry and Psychotherapy, LMU University Hospital, LMU Munich","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1049640","DOI":"10.3389\/fphar.2022.1049640","article-title":"Screening of GPCR drugs for repurposing in breast cancer","volume":"13","author":"Abdulkareem","year":"2022","journal-title":"Front. 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