Tethered agonist- and GAIN domain-independent signaling of an adhesion GPCR.

Overview

1. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA
2. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
3. Division of Life Science, SIAT-HKUST Joint Laboratory for Brain Science, The Hong Kong University of Science and Technology, Hong Kong, China
4. Institute for Stem Cell Biology and Regenerative Medicine, Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA

Abstract

In transfected cells, adhesion G protein–coupled receptors (GPCRs) are activated by tethered agonists that are embedded in their canonical autoproteolytic GAIN domain. It is unknown, however, whether a tethered agonist–dependent activation mechanism generally mediates the physiological functions of adhesion GPCRs. Here, we show that G protein signaling by BAI3 (Adgrb3), a brain-specific adhesion GPCR, is essential for its functions in controlling axon and dendrite growth and promoting synapse formation. Moreover, our signal transduction assays confirm that constitutive exposure of BAI3’s tethered agonist massively stimulates (~5-fold) its GPCR activity. However, the constitutive exposure of BAI3’s tethered agonist, produced by deletion of its extracellular domains, blocked instead of activating BAI3’s functions in regulating axonal and dendritic growth and promoting synapse formation. Moreover, inactivating mutations of BAI3’s tethered agonist or deletion of BAI3’s constituent GAIN domain did not detectably impair BAI3’s physiological functions. Thus, the GPCR activity of BAI3 is functionally required, whereas tethered agonist–mediated stimulation of its GPCR activity is not.

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No code was generated for this study. All data and code needed to evaluate and reproduce the results in the paper are present in the paper and/or the Supplementary Materials, with the complete raw data publicly accessible at https://purl.stanford.edu/bj843yr3863. The plasmids created in this study can be requested from T.C.S. at . No material transfer agreement is required. The BAI3 cKO mice used in this study can be requested from M. Yuzaki at Keio University School of Medicine.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Recorded: type, language, journal, volume, issue, pages, dates, 9 authors, 11 MeSH terms, 6 funders, 58 references.

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This paper

Wang, J., Miao, Y., Wang, J., Zhu, S., Zhang, Y., Wong, T. L., Yousif, A., Wernig, M., & Südhof, T. C. (2026). Tethered agonist- and GAIN domain-independent signaling of an adhesion GPCR. Science advances, 12(27), eadu3822. https://doi.org/10.1126/sciadv.adu3822

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