0587577 - FGÚ 2025 RIV US eng J - Journal Article
Nelic, Dominik - Chetverikov, Nikolai - Hochmalová, Martina - Diaz, Ch. - Doležal, Vladimír - Boulos, J. - Jakubík, Jan - Martemyanov, K. - Janoušková-Randáková, Alena
Agonist-selective activation of individual G-proteins by muscarinic receptors.
Scientific Reports. Roč. 14, č. 1 (2024), č. článku 9652. ISSN 2045-2322. E-ISSN 2045-2322
R&D Projects: GA ČR(CZ) GJ19-06106Y; GA MŠMT(CZ) LX22NPO5104
Institutional support: RVO:67985823
Keywords : muscarinic receptors * binding protein * G-proteins * alpha subunits
OECD category: Pharmacology and pharmacy
Impact factor: 4.6, year: 2022
Method of publishing: Open access
https://doi.org/10.1038/s41598-024-60259-4

Selective activation of individual subtypes of muscarinic receptors is a promising way to safely alleviate a wide range of pathological conditions in the central nervous system and the periphery as well. The flexible G-protein interface of muscarinic receptors allows them to interact with several G-proteins with various efficacy, potency, and kinetics. Agonists biased to the particular G-protein mediated pathway may result in selectivity among muscarinic subtypes and, due to the non-uniform expression of individual G-protein alpha subunits, possibly achieve tissue specificity. Here, we demonstrate that novel tetrahydropyridine-based agonists exert specific signalling profiles in coupling with individual G-protein α subunits. These signalling profiles profoundly differ from the reference agonist carbachol. Moreover, coupling with individual Gα induced by these novel agonists varies among subtypes of muscarinic receptors which may lead to subtype selectivity. Thus, the novel tetrahydropyridine-based agonist can contribute to the elucidation of the mechanism of pathway-specific activation of muscarinic receptors and serve as a starting point for the development of desired selective muscarinic agonists.
Permanent Link: https://hdl.handle.net/11104/0354709