Journal Article

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

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

2020

Overview

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. Gα 12/13 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. Among the adhesion receptor class of GPCRs, which are understudied, the adhesion receptor ADGRL3 can be activated by its own tethered agonist and couples to G protein G12/13 and somewhat to Gq.

• Publisher: Springer Science and Business Media LLC,Nature Publishing Group US,Nature Publishing Group
• Subject: 631/378/340 / 631/80/86 / 631/92/609 / Activating Transcription Factor 6 / Activating Transcription Factor 6 - agonists / Activating Transcription Factor 6 - chemistry / Activating Transcription Factor 6 - genetics / Activating Transcription Factor 6 - metabolism / Adhesion / Agonists / Animals / Arrestin / Arrestin - chemistry / Arrestin - genetics / Arrestin - metabolism / Attention deficit hyperactivity disorder / Biochemical Engineering / Biochemistry / Bioorganic Chemistry / Cell Biology / Cell Engineering / Chemistry / Chemistry and Materials Science / Chemistry/Food Science / CRISPR-Cas Systems / Dopamine / G protein-coupled receptors / Gene Expression / GTP-Binding Protein alpha Subunits, G12-G13 / GTP-Binding Protein alpha Subunits, G12-G13 - chemistry / GTP-Binding Protein alpha Subunits, G12-G13 - genetics / GTP-Binding Protein alpha Subunits, G12-G13 - metabolism / GTP-Binding Protein alpha Subunits, Gq-G11 / GTP-Binding Protein alpha Subunits, Gq-G11 - chemistry / GTP-Binding Protein alpha Subunits, Gq-G11 - genetics / GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism / HEK293 Cells / Humans / Kinetics / Mental disorders / Mice / Mitogen-Activated Protein Kinase 1 / Mitogen-Activated Protein Kinase 1 - chemistry / Mitogen-Activated Protein Kinase 1 - genetics / Mitogen-Activated Protein Kinase 1 - metabolism / Mitogen-Activated Protein Kinase 3 / Mitogen-Activated Protein Kinase 3 - chemistry / Mitogen-Activated Protein Kinase 3 - genetics / Mitogen-Activated Protein Kinase 3 - metabolism / Peptides / Peptides - chemistry / Peptides - metabolism / Peptides - pharmacology / Protein Binding / Proteins / Receptors / Receptors, G-Protein-Coupled / Receptors, G-Protein-Coupled - chemistry / Receptors, G-Protein-Coupled - genetics / Receptors, G-Protein-Coupled - metabolism / Receptors, Peptide / Receptors, Peptide - chemistry / Receptors, Peptide - genetics / Receptors, Peptide - metabolism / Recombinant Proteins / Recombinant Proteins - chemistry / Recombinant Proteins - genetics / Recombinant Proteins - metabolism / Signal Transduction / Signaling / Substance use