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Human GPR17 missense variants identified in metabolic disease patients have distinct downstream signaling profiles

GPR17 is a G-protein-coupled receptor (GPCR) implicated in the regulation of glucose metabolism and energy homeostasis. Such evidence is primarily drawn from mouse knockout studies and suggests GPR17 as a potential novel therapeutic target for the treatment of metabolic diseases. However, links betw...

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Autores principales: Conley, Jason M., Sun, Hongmao, Ayers, Kristin L., Zhu, Hu, Chen, Rong, Shen, Min, Hall, Matthew D., Ren, Hongxia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267566/
https://www.ncbi.nlm.nih.gov/pubmed/34144038
http://dx.doi.org/10.1016/j.jbc.2021.100881
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author Conley, Jason M.
Sun, Hongmao
Ayers, Kristin L.
Zhu, Hu
Chen, Rong
Shen, Min
Hall, Matthew D.
Ren, Hongxia
author_facet Conley, Jason M.
Sun, Hongmao
Ayers, Kristin L.
Zhu, Hu
Chen, Rong
Shen, Min
Hall, Matthew D.
Ren, Hongxia
author_sort Conley, Jason M.
collection PubMed
description GPR17 is a G-protein-coupled receptor (GPCR) implicated in the regulation of glucose metabolism and energy homeostasis. Such evidence is primarily drawn from mouse knockout studies and suggests GPR17 as a potential novel therapeutic target for the treatment of metabolic diseases. However, links between human GPR17 genetic variants, downstream cellular signaling, and metabolic diseases have yet to be reported. Here, we analyzed GPR17 coding sequences from control and disease cohorts consisting of individuals with adverse clinical metabolic deficits including severe insulin resistance, hypercholesterolemia, and obesity. We identified 18 nonsynonymous GPR17 variants, including eight variants that were exclusive to the disease cohort. We characterized the protein expression levels, membrane localization, and downstream signaling profiles of nine GPR17 variants (F43L, V96M, V103M, D105N, A131T, G136S, R248Q, R301H, and G354V). These nine GPR17 variants had similar protein expression and subcellular localization as wild-type GPR17; however, they showed diverse downstream signaling profiles. GPR17-G136S lost the capacity for agonist-mediated cAMP, Ca(2+), and β-arrestin signaling. GPR17-V96M retained cAMP inhibition similar to GPR17-WT, but showed impaired Ca(2+) and β-arrestin signaling. GPR17-D105N displayed impaired cAMP and Ca(2+) signaling, but unaffected agonist-stimulated β-arrestin recruitment. The identification and functional profiling of naturally occurring human GPR17 variants from individuals with metabolic diseases revealed receptor variants with diverse signaling profiles, including differential signaling perturbations that resulted in GPCR signaling bias. Our findings provide a framework for structure–function relationship studies of GPR17 signaling and metabolic disease.
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spelling pubmed-82675662021-07-16 Human GPR17 missense variants identified in metabolic disease patients have distinct downstream signaling profiles Conley, Jason M. Sun, Hongmao Ayers, Kristin L. Zhu, Hu Chen, Rong Shen, Min Hall, Matthew D. Ren, Hongxia J Biol Chem Research Article GPR17 is a G-protein-coupled receptor (GPCR) implicated in the regulation of glucose metabolism and energy homeostasis. Such evidence is primarily drawn from mouse knockout studies and suggests GPR17 as a potential novel therapeutic target for the treatment of metabolic diseases. However, links between human GPR17 genetic variants, downstream cellular signaling, and metabolic diseases have yet to be reported. Here, we analyzed GPR17 coding sequences from control and disease cohorts consisting of individuals with adverse clinical metabolic deficits including severe insulin resistance, hypercholesterolemia, and obesity. We identified 18 nonsynonymous GPR17 variants, including eight variants that were exclusive to the disease cohort. We characterized the protein expression levels, membrane localization, and downstream signaling profiles of nine GPR17 variants (F43L, V96M, V103M, D105N, A131T, G136S, R248Q, R301H, and G354V). These nine GPR17 variants had similar protein expression and subcellular localization as wild-type GPR17; however, they showed diverse downstream signaling profiles. GPR17-G136S lost the capacity for agonist-mediated cAMP, Ca(2+), and β-arrestin signaling. GPR17-V96M retained cAMP inhibition similar to GPR17-WT, but showed impaired Ca(2+) and β-arrestin signaling. GPR17-D105N displayed impaired cAMP and Ca(2+) signaling, but unaffected agonist-stimulated β-arrestin recruitment. The identification and functional profiling of naturally occurring human GPR17 variants from individuals with metabolic diseases revealed receptor variants with diverse signaling profiles, including differential signaling perturbations that resulted in GPCR signaling bias. Our findings provide a framework for structure–function relationship studies of GPR17 signaling and metabolic disease. American Society for Biochemistry and Molecular Biology 2021-06-16 /pmc/articles/PMC8267566/ /pubmed/34144038 http://dx.doi.org/10.1016/j.jbc.2021.100881 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Conley, Jason M.
Sun, Hongmao
Ayers, Kristin L.
Zhu, Hu
Chen, Rong
Shen, Min
Hall, Matthew D.
Ren, Hongxia
Human GPR17 missense variants identified in metabolic disease patients have distinct downstream signaling profiles
title Human GPR17 missense variants identified in metabolic disease patients have distinct downstream signaling profiles
title_full Human GPR17 missense variants identified in metabolic disease patients have distinct downstream signaling profiles
title_fullStr Human GPR17 missense variants identified in metabolic disease patients have distinct downstream signaling profiles
title_full_unstemmed Human GPR17 missense variants identified in metabolic disease patients have distinct downstream signaling profiles
title_short Human GPR17 missense variants identified in metabolic disease patients have distinct downstream signaling profiles
title_sort human gpr17 missense variants identified in metabolic disease patients have distinct downstream signaling profiles
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267566/
https://www.ncbi.nlm.nih.gov/pubmed/34144038
http://dx.doi.org/10.1016/j.jbc.2021.100881
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