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

doi:10.1038/s41589-020-0617-7

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

Pharmacology and Toxicology

Research output: Contribution to journal › Article › peer-review

35 Scopus citations

Abstract

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. [Figure not available: see fulltext.]

Original language	English (US)
Pages (from-to)	1343-1350
Number of pages	8
Journal	Nature Chemical Biology
Volume	16
Issue number	12
DOIs	https://doi.org/10.1038/s41589-020-0617-7
State	Published - Dec 2020

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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title = "G12/13 is activated by acute tethered agonist exposure in the adhesion GPCR ADGRL3",

abstract = "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.]",

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

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2020",

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AU - Mathiasen, Signe

AU - Palmisano, Tiago

AU - Perry, Nicole A.

AU - Stoveken, Hannah M.

AU - Vizurraga, Alex

AU - McEwen, Dyke P.

AU - Okashah, Najeah

AU - Langenhan, Tobias

AU - Inoue, Asuka

AU - Lambert, Nevin A.

AU - Tall, Gregory G.

AU - Javitch, Jonathan A.

PY - 2020/12

Y1 - 2020/12

N2 - 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.]

AB - 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.]

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

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