Your browser doesn't support javascript.
loading
Discovery of a Positive Allosteric Modulator of the Thyrotropin Receptor: Potentiation of Thyrotropin-Mediated Preosteoblast Differentiation In Vitro.
Neumann, Susanne; Eliseeva, Elena; Boutin, Alisa; Barnaeva, Elena; Ferrer, Marc; Southall, Noel; Kim, David; Hu, Xin; Morgan, Sarah J; Marugan, Juan J; Gershengorn, Marvin C.
Afiliación
  • Neumann S; Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (S.N., E.E., A.B., S.J.M., M.C.G.); and Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences, Na
  • Eliseeva E; Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (S.N., E.E., A.B., S.J.M., M.C.G.); and Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences, Na
  • Boutin A; Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (S.N., E.E., A.B., S.J.M., M.C.G.); and Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences, Na
  • Barnaeva E; Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (S.N., E.E., A.B., S.J.M., M.C.G.); and Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences, Na
  • Ferrer M; Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (S.N., E.E., A.B., S.J.M., M.C.G.); and Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences, Na
  • Southall N; Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (S.N., E.E., A.B., S.J.M., M.C.G.); and Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences, Na
  • Kim D; Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (S.N., E.E., A.B., S.J.M., M.C.G.); and Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences, Na
  • Hu X; Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (S.N., E.E., A.B., S.J.M., M.C.G.); and Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences, Na
  • Morgan SJ; Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (S.N., E.E., A.B., S.J.M., M.C.G.); and Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences, Na
  • Marugan JJ; Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (S.N., E.E., A.B., S.J.M., M.C.G.); and Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences, Na
  • Gershengorn MC; Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (S.N., E.E., A.B., S.J.M., M.C.G.); and Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences, Na
J Pharmacol Exp Ther ; 364(1): 38-45, 2018 01.
Article en En | MEDLINE | ID: mdl-29089368
Recently, we showed that TSH-enhanced differentiation of a human preosteoblast-like cell model involved a ß-arrestin 1 (ß-Arr 1)-mediated pathway. To study this pathway in more detail, we sought to discover a small molecule ligand that was functionally selective toward human TSH receptor (TSHR) activation of ß-Arr 1. High-throughput screening using a cell line stably expressing mutated TSHRs and mutated ß-Arr 1 (DiscoverX1 cells) led to the discovery of agonists that stimulated translocation of ß-Arr 1 to the TSHR, but did not activate Gs-mediated signaling pathways, i.e., cAMP production. D3-ßArr (NCGC00379308) was selected. In DiscoverX1 cells, D3-ßArr stimulated ß-Arr 1 translocation with a 5.1-fold greater efficacy than TSH and therefore potentiated the effect of TSH in stimulating ß-Arr 1 translocation. In human U2OS-TSHR cells expressing wild-type TSHRs, which is a model of human preosteoblast-like cells, TSH upregulated the osteoblast-specific genes osteopontin (OPN) and alkaline phosphatase (ALPL). D3-ßArr alone had only a weak effect to upregulate these bone markers, but D3-ßArr potentiated TSH-induced upregulation of ALPL and OPN mRNA levels 1.6-fold and 5.5-fold, respectively, at the maximum dose of ligands. Furthermore, the positive allosteric modulator effect of D3-ßArr resulted in an increase of TSH-induced secretion of OPN protein. In summary, we have discovered the first small molecule positive allosteric modulator of TSHR. As D3-ßArr potentiates the effect of TSH to enhance differentiation of a human preosteoblast in an in vitro model, it will allow a novel experimental approach for probing the role of TSH-induced ß-Arr 1 signaling in osteoblast differentiation.
Asunto(s)
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Osteoblastos / Receptores de Tirotropina / Tirotropina / Diferenciación Celular / Descubrimiento de Drogas Límite: Animals / Humans Idioma: En Revista: J Pharmacol Exp Ther Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Osteoblastos / Receptores de Tirotropina / Tirotropina / Diferenciación Celular / Descubrimiento de Drogas Límite: Animals / Humans Idioma: En Revista: J Pharmacol Exp Ther Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos