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• W2169247152 abstract "To elucidate the pathogenetic mechanisms of a mutant P86S glucagon receptor (GCGR) in causing a novel human disease (Mahvash disease). Enhanced green fluorescent protein (EGFP)-tagged WT and P86S GCGR were expressed in HEK 293 or H1299 cells either transiently or stably. Receptor localization and internalization, and cell apoptosis were studied by fluorescence microscopy, and calcium signaling by Rhod-3 labeling. Gene expression was assayed by RT-PCR or Western blot. Cell fate was determined by live cell imaging. Unlike WT GCGR, P86S was partially localized to the plasma membrane and partially in the cytoplasm as previously reported and did not undergo internalization upon glucagon treatment. P86S did not elicit calcium response after treatment with 1 μM glucagon. Cells transiently expressing P86S exhibited more apoptosis than those expressing WT GCGR (18.3% vs 2.1%, P < 0.05) but the X-box binding protein 1 mRNA cleavage, a marker of endoplasmic reticulum (ER) stress, was not evident, suggesting that the apoptosis did not result from ER stress. Cells stably expressing P86S did not exhibit apoptosis and a quarter of them harbored a novel inclusion body-like circular structure that was marked by P86S and ER residential proteins. These circular ER bodies were not seen in cells expressing WT GCGR or transiently expressing P86S and were not affected by treatment with proteasome inhibitor or microtubule depolymerizer, suggesting that they do not represent aggresome structures. The circular ER bodies could fuse and split to form new bodies. The naturally-occurring P86S mutant GCGR exhibits abnormal receptor internalization and calcium mobilization, and causes apoptosis. The novel dynamic circular ER bodies may be adaptive in nature to nullify the toxic effects on P86S. These findings provide further insights into the pathogenetic mechanisms of Mahvash disease. Conocer los mecanismos patogenéticos de un receptor del glucagón (GCGR) con la mutación P86S en una nueva enfermedad humana (enfermedad de Mahvash). Se expresaron tipos silvestre y P86S del GCGR marcados con proteína verde fluorescente mejorada (EGFP) en células de HEK 293 o H1299 de forma estable o transitoria. Se estudió la localización e internalización del receptor, y la apoptosis celular mediante microscopio de fluorescencia, y la señalización del calcio mediante marcadores Rhod-3. La expresión génica se analizó mediante RT-PCR o Western blot. El destino de la célula se determinó mediante imágenes de las células vivas. A diferencia del tipo silvestre, la mutación P86S se localizó parte en la membrana plasmática y parte en el citoplasma como se ha notificado con anterioridad, y no se produjo internalización tras tratamiento con glucagón. La P86S no indujo respuesta de calcio después del tratamiento con 1 μM de glucagón. Las células que expresaban transitoriamente P86S exhibieron más la apoptosis que aquella con GCGR silvestre (18,3% frente a 2,1%, p < 0,05), pero no resultó patente la existencia de ARNm escindido en proteína de unión X-box 1, un marcador de estrés en el retículo endoplasmático (RE), lo que indica que la apoptosis no fue el resultado de estrés en el RE. Las células que expresan establemente la P86S no mostraron apoptosis y una cuarta parte de ellas albergaba la inclusión de una estructura circular corpusculoide nueva marcada por P86S y proteínas residentes del RE. Estos cuerpos circulares no se observaron en las células que expresaban GCGR silvestre o transitoriamente P86S y no se vieron afectados por el tratamiento con el inhibidor del proteasoma o despolimerizador microtubular, lo que sugiere que no representan estructuras agresivas. Los cuerpos circulares en RE podían fusionarse y dividirse para formar nuevos cuerpos. La mutación natural P86S de GCGR muestra una internalización anormal del receptor y de la movilización de calcio, y causa apoptosis. Los nuevos cuerpos circulares y dinámicos en el RE puede que sean una respuesta adaptativa para anular los efectos tóxicos sobre P86S. Estos hallazgos proporcionan nuevas perspectivas sobre la patogénesis de la enfermedad de Mahvash." @default.
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• W2169247152 date "2011-06-01" @default.
• W2169247152 modified "2023-10-17" @default.
• W2169247152 title "A natural inactivating mutant of human glucagon receptor exhibits multiple abnormalities in processing and signaling" @default.
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• W2169247152 doi "https://doi.org/10.1016/j.endonu.2011.04.002" @default.
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