G12/13 is activated by acute tethered agonist exposure in the adhesion GPCR ADGRL3

Signe Mathiasen, Tiago Palmisano, Nicole A. Perry, Hannah M. Stoveken, Alex Vizurraga, Dyke P. McEwen, Najeah Okashah, Tobias Langenhan, Asuka Inoue, Nevin A. Lambert, Gregory G. Tall, Jonathan A. Javitch

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)


The adhesion G-protein-coupled receptor (GPCR) latrophilin 3 (ADGRL3) has been associated with increased risk of attention deficit hyperactivity disorder (ADHD) and substance use in human genetic studies. Knockdown in multiple species leads to hyperlocomotion and altered dopamine signaling. Thus, ADGRL3 is a potential target for treatment of neuropsychiatric disorders that involve dopamine dysfunction, but its basic signaling properties are poorly understood. Identification of adhesion GPCR signaling partners has been limited by a lack of tools to acutely activate these receptors in living cells. Here, we design a novel acute activation strategy to characterize ADGRL3 signaling by engineering a receptor construct in which we could trigger acute activation enzymatically. Using this assay, we found that ADGRL3 signals through G12/G13 and Gq, with G12/13 the most robustly activated. Gα12/13 is a new player in ADGRL3 biology, opening up unexplored roles for ADGRL3 in the brain. Our methodological advancements should be broadly useful in adhesion GPCR research. [Figure not available: see fulltext.]

Original languageEnglish
Pages (from-to)1343-1350
Number of pages8
JournalNature Chemical Biology
Issue number12
Publication statusPublished - 2020 Dec


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