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Dissociation of the G protein βγ from the Gq–PLCβ complex partially attenuates PIP2 hydrolysis

Phospholipase C β (PLCβ), which is activated by the Gq family of heterotrimeric G proteins, hydrolyzes the inner membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2), generating diacylglycerol and inositol 1,4,5-triphosphate (IP3). Because Gq and PLCβ regulate many crucial cellular processes...

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Autores principales: Kankanamge, Dinesh, Ubeysinghe, Sithurandi, Tennakoon, Mithila, Pantula, Priyanka Devi, Mitra, Kishalay, Giri, Lopamudra, Karunarathne, Ajith
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/PMC8138763/
https://www.ncbi.nlm.nih.gov/pubmed/33901492
http://dx.doi.org/10.1016/j.jbc.2021.100702
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author Kankanamge, Dinesh
Ubeysinghe, Sithurandi
Tennakoon, Mithila
Pantula, Priyanka Devi
Mitra, Kishalay
Giri, Lopamudra
Karunarathne, Ajith
author_facet Kankanamge, Dinesh
Ubeysinghe, Sithurandi
Tennakoon, Mithila
Pantula, Priyanka Devi
Mitra, Kishalay
Giri, Lopamudra
Karunarathne, Ajith
author_sort Kankanamge, Dinesh
collection PubMed
description Phospholipase C β (PLCβ), which is activated by the Gq family of heterotrimeric G proteins, hydrolyzes the inner membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2), generating diacylglycerol and inositol 1,4,5-triphosphate (IP3). Because Gq and PLCβ regulate many crucial cellular processes and have been identified as major disease drivers, activation and termination of PLCβ signaling by the Gαq subunit have been extensively studied. Gq-coupled receptor activation induces intense and transient PIP2 hydrolysis, which subsequently recovers to a low-intensity steady-state equilibrium. However, the molecular underpinnings of this equilibrium remain unclear. Here, we explored the influence of signaling crosstalk between Gq and Gi/o pathways on PIP2 metabolism in living cells using single-cell and optogenetic approaches to spatially and temporally constrain signaling. Our data suggest that the Gβγ complex is a component of the highly efficient lipase Gαq(GTP)–PLCβ–Gβγ. We found that over time, Gβγ dissociates from this lipase complex, leaving the less-efficient Gαq(GTP)–PLCβ lipase complex and allowing the significant partial recovery of PIP2 levels. Our findings also indicate that the subtype of the Gγ subunit in Gβγ fine-tunes the lipase activity of Gq–PLCβ, in which cells expressing Gγ with higher plasma membrane interaction show lower PIP2 recovery. Given that Gγ shows cell- and tissue-specific subtype expression, our findings suggest the existence of tissue-specific distinct Gq–PLCβ signaling paradigms. Furthermore, these results also outline a molecular process that likely safeguards cells from excessive Gq signaling.
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spelling pubmed-81387632021-05-24 Dissociation of the G protein βγ from the Gq–PLCβ complex partially attenuates PIP2 hydrolysis Kankanamge, Dinesh Ubeysinghe, Sithurandi Tennakoon, Mithila Pantula, Priyanka Devi Mitra, Kishalay Giri, Lopamudra Karunarathne, Ajith J Biol Chem Research Article Phospholipase C β (PLCβ), which is activated by the Gq family of heterotrimeric G proteins, hydrolyzes the inner membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2), generating diacylglycerol and inositol 1,4,5-triphosphate (IP3). Because Gq and PLCβ regulate many crucial cellular processes and have been identified as major disease drivers, activation and termination of PLCβ signaling by the Gαq subunit have been extensively studied. Gq-coupled receptor activation induces intense and transient PIP2 hydrolysis, which subsequently recovers to a low-intensity steady-state equilibrium. However, the molecular underpinnings of this equilibrium remain unclear. Here, we explored the influence of signaling crosstalk between Gq and Gi/o pathways on PIP2 metabolism in living cells using single-cell and optogenetic approaches to spatially and temporally constrain signaling. Our data suggest that the Gβγ complex is a component of the highly efficient lipase Gαq(GTP)–PLCβ–Gβγ. We found that over time, Gβγ dissociates from this lipase complex, leaving the less-efficient Gαq(GTP)–PLCβ lipase complex and allowing the significant partial recovery of PIP2 levels. Our findings also indicate that the subtype of the Gγ subunit in Gβγ fine-tunes the lipase activity of Gq–PLCβ, in which cells expressing Gγ with higher plasma membrane interaction show lower PIP2 recovery. Given that Gγ shows cell- and tissue-specific subtype expression, our findings suggest the existence of tissue-specific distinct Gq–PLCβ signaling paradigms. Furthermore, these results also outline a molecular process that likely safeguards cells from excessive Gq signaling. American Society for Biochemistry and Molecular Biology 2021-04-24 /pmc/articles/PMC8138763/ /pubmed/33901492 http://dx.doi.org/10.1016/j.jbc.2021.100702 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
Kankanamge, Dinesh
Ubeysinghe, Sithurandi
Tennakoon, Mithila
Pantula, Priyanka Devi
Mitra, Kishalay
Giri, Lopamudra
Karunarathne, Ajith
Dissociation of the G protein βγ from the Gq–PLCβ complex partially attenuates PIP2 hydrolysis
title Dissociation of the G protein βγ from the Gq–PLCβ complex partially attenuates PIP2 hydrolysis
title_full Dissociation of the G protein βγ from the Gq–PLCβ complex partially attenuates PIP2 hydrolysis
title_fullStr Dissociation of the G protein βγ from the Gq–PLCβ complex partially attenuates PIP2 hydrolysis
title_full_unstemmed Dissociation of the G protein βγ from the Gq–PLCβ complex partially attenuates PIP2 hydrolysis
title_short Dissociation of the G protein βγ from the Gq–PLCβ complex partially attenuates PIP2 hydrolysis
title_sort dissociation of the g protein βγ from the gq–plcβ complex partially attenuates pip2 hydrolysis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138763/
https://www.ncbi.nlm.nih.gov/pubmed/33901492
http://dx.doi.org/10.1016/j.jbc.2021.100702
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