TY - JOUR
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.
N1 - Funding Information:
This work was supported by NIH grants MH112156 (J.A.J.), GM130142 (N.A.L.), GM131672 (N.O.) and T32-GM007315 (A.V.), and by the Hope for Depression Research Foundation (J.A.J.). A.I. was funded by PRIME 18gm5910013 and LEAP 18gm0010004 from the Japan Agency for Medical Research and Development (AMED) and KAKENHI 17K08264 from the Japan Society for the Promotion of Science (JSPS). T.L. was funded by the Deutsche Forschungsgemeinschaft through FOR2149 project P01 [LA2861/4-2] and CRC 1423, project number 421152132, subprojects A06, B06. We thank L. Lavis and J.B. Grimm (Janelia Research Campus) for generously providing the JF-525 and JF-646 fluorophores.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
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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U2 - 10.1038/s41589-020-0617-7
DO - 10.1038/s41589-020-0617-7
M3 - Article
C2 - 32778842
AN - SCOPUS:85089252778
SN - 1552-4450
VL - 16
SP - 1343
EP - 1350
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 12
ER -