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

E. Dolejší, N. Chetverikov, E. Szánti-Pintér, D. Nelic, A. Randáková, V. Doležal, EE. El-Fakahany, E. Kudová, J. Jakubík

. 2021 ; 192 (-) : 114699. [pub] 20210726

Language English Country Great Britain

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc22003529

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 µM. 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 alcuronium 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..

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$a Endogenous neurosteroids and their synthetic analogues-neuroactive steroids-have been found to bind to muscarinic acetylcholine receptors and allosterically modulate acetylcholine binding and function. Using radioligand binding experiments we investigated their binding mode. We show that neuroactive steroids bind to two binding sites on muscarinic receptors. Their affinity for the high-affinity binding site is about 100 nM. Their affinity for the low-affinity binding site is about 10 µM. The high-affinity binding occurs at the same site as binding of steroid-based WIN-compounds that is different from the common allosteric binding site for alcuronium or gallamine that is located between the second and third extracellular loop of the receptor. This binding site is also different from the allosteric binding site for the structurally related aminosteroid-based myorelaxants pancuronium and rapacuronium. Membrane cholesterol competes with neurosteroids/neuroactive steroids binding to both high- and low-affinity binding site, indicating that both sites are oriented towards the cell membrane..
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$a Chetverikov, Nikolai $u Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
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$a Nelic, Dominik $u Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
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$a Randáková, Alena $u Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
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$a Kudová, Eva $u Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic. Electronic address: eva.kudova@uochb.cas.cz
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$a Jakubík, Jan $u Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic. Electronic address: jan.jakubik@fgu.cas.cz
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