G12/13 is activated by acute tethered agonist exposure in the adhesion GPCR ADGRL3
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G12/13 is activated by acute tethered agonist exposure in the adhesion GPCR ADGRL3. / Mathiasen, Signe; Palmisano, Tiago; Perry, Nicole A.; Stoveken, Hannah M.; Vizurraga, Alex; McEwen, Dyke P.; Okashah, Najeah; Langenhan, Tobias; Inoue, Asuka; Lambert, Nevin A.; Tall, Gregory G.; Javitch, Jonathan A.
I: Nature Chemical Biology, Bind 16, Nr. 12, 12.2020, s. 1343–1350 .Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - G12/13 is activated by acute tethered agonist exposure in the adhesion GPCR ADGRL3
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. G alpha(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.
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. G alpha(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.
KW - PROTEIN-COUPLED RECEPTORS
KW - CELL-ADHESION
KW - LATROPHILIN
KW - GPR56
KW - ADHD
KW - IDENTIFICATION
KW - FORSKOLIN
KW - TERMINUS
KW - LIGANDS
KW - GPR126
U2 - 10.1038/s41589-020-0617-7
DO - 10.1038/s41589-020-0617-7
M3 - Journal article
VL - 16
SP - 1343
EP - 1350
JO - Nature Chemical Biology
JF - Nature Chemical Biology
SN - 1552-4450
IS - 12
ER -
ID: 311723150