Fusion with Promiscuous G alpha(16) Subunit Reveals Signaling Bias at Muscarinic Receptors

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F21%3A00546460" target="_blank" >RIV/67985823:_____/21:00546460 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.mdpi.com/1422-0067/22/18/10089" target="_blank" >https://www.mdpi.com/1422-0067/22/18/10089</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3390/ijms221810089" target="_blank" >10.3390/ijms221810089</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Fusion with Promiscuous G alpha(16) Subunit Reveals Signaling Bias at Muscarinic Receptors

Popis výsledku v původním jazyce

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 alpha-subunit of G(16) protein to study agonist bias. We have demonstrated that fusion of muscarinic receptors with G alpha(16) limits access of other competitive G alpha subunits to the receptor, and thus enables us to study activation of G alpha(16) mediated pathway more specifically. Our data demonstrated agonist-specific activation of G(16) pathway among individual subtypes of muscarinic receptors and revealed signaling bias of oxotremorine towards G alpha(16) pathway at the M-2 receptor and at the same time impaired G alpha(16) signaling of iperoxo at M-5 receptors. Our data have shown that fusion proteins of muscarinic receptors with alpha-subunit of G-proteins can serve as a suitable tool for studying agonist bias, especially at non-preferential pathways.

Název v anglickém jazyce

Fusion with Promiscuous G alpha(16) Subunit Reveals Signaling Bias at Muscarinic Receptors

Popis výsledku anglicky

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 alpha-subunit of G(16) protein to study agonist bias. We have demonstrated that fusion of muscarinic receptors with G alpha(16) limits access of other competitive G alpha subunits to the receptor, and thus enables us to study activation of G alpha(16) mediated pathway more specifically. Our data demonstrated agonist-specific activation of G(16) pathway among individual subtypes of muscarinic receptors and revealed signaling bias of oxotremorine towards G alpha(16) pathway at the M-2 receptor and at the same time impaired G alpha(16) signaling of iperoxo at M-5 receptors. Our data have shown that fusion proteins of muscarinic receptors with alpha-subunit of G-proteins can serve as a suitable tool for studying agonist bias, especially at non-preferential pathways.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

<a href="/cs/project/GJ19-06106Y" target="_blank" >GJ19-06106Y: Analýza signalizačního biasu nově syntetizovaných muskarinových agonistů</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

International Journal of Molecular Sciences

ISSN

1422-0067

e-ISSN

1422-0067

Svazek periodika

22

Číslo periodika v rámci svazku

18

Stát vydavatele periodika

CH - Švýcarská konfederace

Počet stran výsledku

20

Strana od-do

10089

Kód UT WoS článku

000699826600001

EID výsledku v databázi Scopus

2-s2.0-85115086361