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Functional Heterodimerization between the G Protein-Coupled Receptor GPR17 and the Chemokine Receptors 2 and 4: New Evidence

GPR17, a G protein-coupled receptor, is a pivotal regulator of myelination. Its endogenous ligands trigger receptor desensitization and downregulation allowing oligodendrocyte terminal maturation. In addition to its endogenous agonists, GPR17 could be promiscuously activated by pro-inflammatory oxys...

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Autores principales: Daniele, Simona, Saporiti, Simona, Capaldi, Stefano, Pietrobono, Deborah, Russo, Lara, Guerrini, Uliano, Laurenzi, Tommaso, Ataie Kachoie, Elham, Palazzolo, Luca, Russo, Vincenzo, Abbracchio, Maria Pia, Eberini, Ivano, Trincavelli, Maria Letizia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9820414/
https://www.ncbi.nlm.nih.gov/pubmed/36613703
http://dx.doi.org/10.3390/ijms24010261
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author Daniele, Simona
Saporiti, Simona
Capaldi, Stefano
Pietrobono, Deborah
Russo, Lara
Guerrini, Uliano
Laurenzi, Tommaso
Ataie Kachoie, Elham
Palazzolo, Luca
Russo, Vincenzo
Abbracchio, Maria Pia
Eberini, Ivano
Trincavelli, Maria Letizia
author_facet Daniele, Simona
Saporiti, Simona
Capaldi, Stefano
Pietrobono, Deborah
Russo, Lara
Guerrini, Uliano
Laurenzi, Tommaso
Ataie Kachoie, Elham
Palazzolo, Luca
Russo, Vincenzo
Abbracchio, Maria Pia
Eberini, Ivano
Trincavelli, Maria Letizia
author_sort Daniele, Simona
collection PubMed
description GPR17, a G protein-coupled receptor, is a pivotal regulator of myelination. Its endogenous ligands trigger receptor desensitization and downregulation allowing oligodendrocyte terminal maturation. In addition to its endogenous agonists, GPR17 could be promiscuously activated by pro-inflammatory oxysterols and chemokines released at demyelinating lesions. Herein, the chemokine receptors CXCR2 and CXCR4 were selected to perform both in silico modelling and in vitro experiments to establish their structural and functional interactions with GPR17. The relative propensity of GPR17 and CXCR2 or CXCR4 to form homo- and hetero-dimers was assessed by homology modelling and molecular dynamics (MD) simulations, and co-immunoprecipitation and immunoenzymatic assay. The interaction between chemokine receptors and GPR17 was investigated by determining receptor-mediated modulation of intracellular cyclic adenosine monophosphate (cAMP). Our data show the GPR17 association with CXCR2 or CXCR4 and the negative regulation of these interactions by CXCR agonists or antagonists. Moreover, GPR17 and CXCR2 heterodimers can functionally influence each other. In contrast, CXCR4 can influence GPR17 functionality, but not vice versa. According to MD simulations, all the dimers reached conformational stability and negative formation energy, confirming the experimental observations. The cross-talk between these receptors could play a role in the development of the neuroinflammatory milieu associated with demyelinating events.
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spelling pubmed-98204142023-01-07 Functional Heterodimerization between the G Protein-Coupled Receptor GPR17 and the Chemokine Receptors 2 and 4: New Evidence Daniele, Simona Saporiti, Simona Capaldi, Stefano Pietrobono, Deborah Russo, Lara Guerrini, Uliano Laurenzi, Tommaso Ataie Kachoie, Elham Palazzolo, Luca Russo, Vincenzo Abbracchio, Maria Pia Eberini, Ivano Trincavelli, Maria Letizia Int J Mol Sci Article GPR17, a G protein-coupled receptor, is a pivotal regulator of myelination. Its endogenous ligands trigger receptor desensitization and downregulation allowing oligodendrocyte terminal maturation. In addition to its endogenous agonists, GPR17 could be promiscuously activated by pro-inflammatory oxysterols and chemokines released at demyelinating lesions. Herein, the chemokine receptors CXCR2 and CXCR4 were selected to perform both in silico modelling and in vitro experiments to establish their structural and functional interactions with GPR17. The relative propensity of GPR17 and CXCR2 or CXCR4 to form homo- and hetero-dimers was assessed by homology modelling and molecular dynamics (MD) simulations, and co-immunoprecipitation and immunoenzymatic assay. The interaction between chemokine receptors and GPR17 was investigated by determining receptor-mediated modulation of intracellular cyclic adenosine monophosphate (cAMP). Our data show the GPR17 association with CXCR2 or CXCR4 and the negative regulation of these interactions by CXCR agonists or antagonists. Moreover, GPR17 and CXCR2 heterodimers can functionally influence each other. In contrast, CXCR4 can influence GPR17 functionality, but not vice versa. According to MD simulations, all the dimers reached conformational stability and negative formation energy, confirming the experimental observations. The cross-talk between these receptors could play a role in the development of the neuroinflammatory milieu associated with demyelinating events. MDPI 2022-12-23 /pmc/articles/PMC9820414/ /pubmed/36613703 http://dx.doi.org/10.3390/ijms24010261 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Daniele, Simona
Saporiti, Simona
Capaldi, Stefano
Pietrobono, Deborah
Russo, Lara
Guerrini, Uliano
Laurenzi, Tommaso
Ataie Kachoie, Elham
Palazzolo, Luca
Russo, Vincenzo
Abbracchio, Maria Pia
Eberini, Ivano
Trincavelli, Maria Letizia
Functional Heterodimerization between the G Protein-Coupled Receptor GPR17 and the Chemokine Receptors 2 and 4: New Evidence
title Functional Heterodimerization between the G Protein-Coupled Receptor GPR17 and the Chemokine Receptors 2 and 4: New Evidence
title_full Functional Heterodimerization between the G Protein-Coupled Receptor GPR17 and the Chemokine Receptors 2 and 4: New Evidence
title_fullStr Functional Heterodimerization between the G Protein-Coupled Receptor GPR17 and the Chemokine Receptors 2 and 4: New Evidence
title_full_unstemmed Functional Heterodimerization between the G Protein-Coupled Receptor GPR17 and the Chemokine Receptors 2 and 4: New Evidence
title_short Functional Heterodimerization between the G Protein-Coupled Receptor GPR17 and the Chemokine Receptors 2 and 4: New Evidence
title_sort functional heterodimerization between the g protein-coupled receptor gpr17 and the chemokine receptors 2 and 4: new evidence
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9820414/
https://www.ncbi.nlm.nih.gov/pubmed/36613703
http://dx.doi.org/10.3390/ijms24010261
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