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Fusion with Promiscuous Gα16 Subunit Reveals Signaling Bias at Muscarinic Receptors
A. Randáková, D. Nelic, M. Hochmalová, P. Zimčík, MJ. Mulenga, J. Boulos, J. Jakubík
Jazyk angličtina Země Švýcarsko
Typ dokumentu časopisecké články
Grantová podpora
19-06106Y
Grantová Agentura České Republiky
RVO:67985823
Akademie Věd České Republiky
Free Medical Journals od 2000
Freely Accessible Science Journals od 2000
PubMed Central od 2007
Europe PubMed Central od 2007
ProQuest Central od 2000-03-01
Open Access Digital Library od 2000-01-01
Open Access Digital Library od 2007-01-01
Health & Medicine (ProQuest) od 2000-03-01
ROAD: Directory of Open Access Scholarly Resources od 2000
Odkazy
PubMed
34576254
DOI
10.3390/ijms221810089
Knihovny.cz E-zdroje
- MeSH
- AMP cyklický metabolismus MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- inhibiční koncentrace 50 MeSH
- isoxazoly chemie MeSH
- křečci praví MeSH
- kvartérní amoniové sloučeniny chemie MeSH
- lidé MeSH
- molekulární konformace MeSH
- oxotremorin chemie MeSH
- proteiny vázající GTP - alfa-podjednotky Gq-G11 metabolismus MeSH
- receptory muskarinové metabolismus MeSH
- rekombinantní fúzní proteiny chemie MeSH
- signální transdukce * MeSH
- simulace molekulární dynamiky MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
A complex evaluation of agonist bias at G-protein coupled receptors at the level of G-protein classes and isoforms including non-preferential ones is essential for advanced agonist screening and drug development. Molecular crosstalk in downstream signaling and a lack of sufficiently sensitive and selective methods to study direct coupling with G-protein of interest complicates this analysis. We performed binding and functional analysis of 11 structurally different agonists on prepared fusion proteins of individual subtypes of muscarinic receptors and non-canonical promiscuous α-subunit of G16 protein to study agonist bias. We have demonstrated that fusion of muscarinic receptors with Gα16 limits access of other competitive Gα subunits to the receptor, and thus enables us to study activation of Gα16 mediated pathway more specifically. Our data demonstrated agonist-specific activation of G16 pathway among individual subtypes of muscarinic receptors and revealed signaling bias of oxotremorine towards Gα16 pathway at the M2 receptor and at the same time impaired Gα16 signaling of iperoxo at M5 receptors. Our data have shown that fusion proteins of muscarinic receptors with α-subunit of G-proteins can serve as a suitable tool for studying agonist bias, especially at non-preferential pathways.
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- $a A complex evaluation of agonist bias at G-protein coupled receptors at the level of G-protein classes and isoforms including non-preferential ones is essential for advanced agonist screening and drug development. Molecular crosstalk in downstream signaling and a lack of sufficiently sensitive and selective methods to study direct coupling with G-protein of interest complicates this analysis. We performed binding and functional analysis of 11 structurally different agonists on prepared fusion proteins of individual subtypes of muscarinic receptors and non-canonical promiscuous α-subunit of G16 protein to study agonist bias. We have demonstrated that fusion of muscarinic receptors with Gα16 limits access of other competitive Gα subunits to the receptor, and thus enables us to study activation of Gα16 mediated pathway more specifically. Our data demonstrated agonist-specific activation of G16 pathway among individual subtypes of muscarinic receptors and revealed signaling bias of oxotremorine towards Gα16 pathway at the M2 receptor and at the same time impaired Gα16 signaling of iperoxo at M5 receptors. Our data have shown that fusion proteins of muscarinic receptors with α-subunit of G-proteins can serve as a suitable tool for studying agonist bias, especially at non-preferential pathways.
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