Neuroactive steroids, WIN-compounds and cholesterol share a common binding site on muscarinic acetylcholine receptors

0546864 - FGÚ 2022 RIV US eng J - Článek v odborném periodiku
Dolejší, Eva - Chetverikov, Nikolai - Szánti-Pintér, Eszter - Nelic, Dominik - Randáková, Alena - Doležal, Vladimír - El-Fakahany, E. E. - Kudová, Eva - Jakubík, Jan
Neuroactive steroids, WIN-compounds and cholesterol share a common binding site on muscarinic acetylcholine receptors.
Biochemical Pharmacology. Roč. 192, Oct (2021), č. článku 114699. ISSN 0006-2952. E-ISSN 1873-2968
Grant CEP: GA ČR(CZ) GA19-05318S
Grant ostatní: AV ČR(CZ) StrategieAV21/10
Program: StrategieAV
Institucionální podpora: RVO:67985823 ; RVO:61388963
Klíčová slova: neuroactive steroids * cholesterol * muscarinic receptors * allosteric modulation
Obor OECD: Physiology (including cytology); Physiology (including cytology) (UOCHB-X)
Impakt faktor: 6.100, rok: 2021
Způsob publikování: Open access
https://doi.org/10.1016/j.bcp.2021.114699

Endogenous neurosteroids and their synthetic analogues-neuroactive steroids-have been found to bind to muscarinic acetylcholine receptors and allosterically modulate acetylcholine binding and function. Using radioligand binding experiments we investigated their binding mode. We show that neuroactive steroids bind to two binding sites on muscarinic receptors. Their affinity for the high-affinity binding site is about 100 nM. Their affinity for the low-affinity binding site is about 10 mu M. The high-affinity binding occurs at the same site as binding of steroid-based WIN-compounds that is different from the common allosteric binding site for alcumnium or gallamine that is located between the second and third extracellular loop of the receptor. This binding site is also different from the allosteric binding site for the structurally related aminosteroid-based myorelaxants pancuronium and rapacuronium. Membrane cholesterol competes with neurosteroids/neuroactive steroids binding to both high- and low-affinity binding site, indicating that both sites are oriented towards the cell membrane.
Trvalý link: http://hdl.handle.net/11104/0323241