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..
- MeSH
- alosterická regulace účinky léků fyziologie MeSH
- androstany metabolismus farmakologie MeSH
- androsteny metabolismus farmakologie MeSH
- benzimidazoly metabolismus farmakologie MeSH
- CHO buňky MeSH
- cholesterol metabolismus MeSH
- Cricetulus MeSH
- křečci praví MeSH
- lidé MeSH
- nervosvalové látky nedepolarizující metabolismus farmakologie MeSH
- neurosteroidy metabolismus MeSH
- receptory muskarinové metabolismus MeSH
- triethojodid gallaminia metabolismus farmakologie MeSH
- vazebná místa účinky léků fyziologie MeSH
- vekuronium analogy a deriváty metabolismus farmakologie MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- alkuronium farmakologie metabolismus MeSH
- jedy farmakologie metabolismus MeSH
- krysa rodu rattus MeSH
- myokard metabolismus ultrasonografie MeSH
- receptory muskarinové metabolismus účinky léků MeSH
- skopolaminové deriváty metabolismus MeSH
- strychnin farmakologie metabolismus MeSH
- triethojodid gallaminia farmakologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH