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

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.

Afiliación

Mathiasen S; Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
Palmisano T; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA.
Perry NA; Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
Stoveken HM; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA.
Vizurraga A; Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
McEwen DP; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA.
Okashah N; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
Langenhan T; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
Inoue A; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
Lambert NA; Department of Pharmacology and Toxicology, Augusta University Medical College of Georgia, Augusta, GA, USA.
Tall GG; Rudolf Schönheimer Institute of Biochemistry, Division of General Biochemistry, Medical Faculty, Leipzig University, Leipzig, Germany.
Javitch JA; Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.

Nat Chem Biol ; 16(12): 1343-1350, 2020 12.

Article en En | MEDLINE | ID: mdl-32778842

RESUMEN

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.

Asunto(s)

Factor de Transcripción Activador 6/metabolismo; Subunidades alfa de la Proteína de Unión al GTP G12-G13/metabolismo; Péptidos/metabolismo; Receptores Acoplados a Proteínas G/metabolismo; Receptores de Péptidos/metabolismo; Factor de Transcripción Activador 6/agonistas; Factor de Transcripción Activador 6/química; Factor de Transcripción Activador 6/genética; Animales; Arrestina/química; Arrestina/genética; Arrestina/metabolismo; Sistemas CRISPR-Cas; Ingeniería Celular; Subunidades alfa de la Proteína de Unión al GTP G12-G13/química; Subunidades alfa de la Proteína de Unión al GTP G12-G13/genética; Subunidades alfa de la Proteína de Unión al GTP Gq-G11/química; Subunidades alfa de la Proteína de Unión al GTP Gq-G11/genética; Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo; Expresión Génica; Células HEK293; Humanos; Cinética; Ratones; Proteína Quinasa 1 Activada por Mitógenos/química; Proteína Quinasa 1 Activada por Mitógenos/genética; Proteína Quinasa 1 Activada por Mitógenos/metabolismo; Proteína Quinasa 3 Activada por Mitógenos/química; Proteína Quinasa 3 Activada por Mitógenos/genética; Proteína Quinasa 3 Activada por Mitógenos/metabolismo; Péptidos/química; Péptidos/farmacología; Unión Proteica; Receptores Acoplados a Proteínas G/química; Receptores Acoplados a Proteínas G/genética; Receptores de Péptidos/química; Receptores de Péptidos/genética; Proteínas Recombinantes/química; Proteínas Recombinantes/genética; Proteínas Recombinantes/metabolismo; Transducción de Señal

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos / Receptores de Péptidos / Subunidades alfa de la Proteína de Unión al GTP G12-G13 / Receptores Acoplados a Proteínas G / Factor de Transcripción Activador 6 Tipo de estudio: Prognostic_studies Idioma: En Revista: Nat Chem Biol Asunto de la revista: BIOLOGIA / QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

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