{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T02:09:23Z","timestamp":1791857363296,"version":"4.3.4"},"reference-count":38,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"887","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2025,5,20]]},"abstract":"<jats:p>\n            G protein\u2013coupled receptors (GPCRs) are transmembrane detectors of extracellular signals that activate heterotrimeric G proteins to regulate intracellular responses. Because there are only 16 G\u03b1 proteins that can couple to GPCRs, variation in a single G\u03b1 can affect the function of numerous receptors. Here, we investigated two mutant forms of G\u03b1\n            <jats:sub>s<\/jats:sub>\n            (L388R and E392K) that are associated with pseudohypoparathyroidism type Ic (PHPIc), a maternally inherited rare disease. G\u03b1\n            <jats:sub>s<\/jats:sub>\n            is encoded by an imprinted gene, resulting in the mutant form of G\u03b1\n            <jats:sub>s<\/jats:sub>\n            being the only version of the protein present in certain tissues, which leads to tissue-specific disease manifestations. By integrating data from three-dimensional structures, GPCR\u2013G protein coupling specificity, transcriptomics, biophysics, and molecular dynamics with systems pharmacology modeling, we identified GPCRs whose signaling could be altered by G\u03b1\n            <jats:sub>s<\/jats:sub>\n            mutations in the kidney, a tissue involved in the pathophysiology of PHPIc. Analysis of G protein activation by the parathyroid hormone receptor 1 (PTH1R) revealed that L388R impaired G\u03b1\n            <jats:sub>s<\/jats:sub>\n            interaction with the receptor, whereas E392K reduced the receptor-induced activation of heterotrimeric G\n            <jats:sub>s<\/jats:sub>\n            . This indicates that different signal transduction steps can be altered by specific G\u03b1\n            <jats:sub>s<\/jats:sub>\n            mutants associated with the same disease. These findings highlight the importance of investigating mutation-specific perturbations in GPCR signaling to suggest patient-specific treatment strategies. Furthermore, our methods provide a blueprint for interrogating GPCR signaling diversity in different physiological and pathophysiological contexts.\n          <\/jats:p>","DOI":"10.1126\/scisignal.ado7543","type":"journal-article","created":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T17:58:23Z","timestamp":1747763903000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":8,"title":["Loss-of-function G\u03b1\n            <sub>s<\/sub>\n            rare disease variants exert mutation-specific effects on GPCR signaling"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7503-4510","authenticated-orcid":true,"given":"Theo","family":"Redfern-Nichols","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3265-6998","authenticated-orcid":true,"given":"Shannon L.","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"Department of Metabolism and Systems Science, College of Medicine and Health, University of Birmingham, Birmingham B15 2TT, UK."},{"name":"Centre of Membrane Proteins and Receptors (COMPARE), Universities of Nottingham and Birmingham, Birmingham B15 2TT, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2947-7638","authenticated-orcid":true,"given":"Xianglin","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2831-7731","authenticated-orcid":true,"given":"Brian","family":"Medel-Lacruz","sequence":"additional","affiliation":[{"name":"Research Programme on Biomedical Informatics, Hospital del Mar Medical Research Institute, Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, 08003, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3811-1553","authenticated-orcid":true,"given":"Davide","family":"Calebiro","sequence":"additional","affiliation":[{"name":"Department of Metabolism and Systems Science, College of Medicine and Health, University of Birmingham, Birmingham B15 2TT, UK."},{"name":"Centre of Membrane Proteins and Receptors (COMPARE), Universities of Nottingham and Birmingham, Birmingham B15 2TT, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1844-4449","authenticated-orcid":true,"given":"Jana","family":"Selent","sequence":"additional","affiliation":[{"name":"Research Programme on Biomedical Informatics, Hospital del Mar Medical Research Institute, Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, 08003, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7320-9612","authenticated-orcid":true,"given":"Graham","family":"Ladds","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0373-8927","authenticated-orcid":true,"given":"Maria","family":"Marti-Solano","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Cambridge, Tennis 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