Počet záznamů: 1

Role of membrane cholesterol in differential sensitivity of muscarinic receptor subtypes to persistently bound xanomeline

SYSNO ASEP	0489273
Druh ASEP	J - Článek v odborném periodiku
Zařazení RIV	J - Článek v odborném periodiku
Poddruh J	Článek ve WOS
Název	Role of membrane cholesterol in differential sensitivity of muscarinic receptor subtypes to persistently bound xanomeline
Tvůrce(i)	Randáková, Alena (FGU-C)_{RID, ORCID} Dolejší, Eva (FGU-C)_{RID, ORCID} Rudajev, Vladimír (FGU-C)_RID Zimčík, Pavel (FGU-C) Doležal, Vladimír (FGU-C)_{RID, ORCID} El-Fakahany, E. E. (US) Jakubík, Jan (FGU-C)_{RID, ORCID}
Zdroj.dok.	Neuropharmacology. - : Elsevier - ISSN 0028-3908 Roč. 133, May 1 (2018), s. 129-144
Poč.str.	16 s.
Jazyk dok.	eng - angličtina
Země vyd.	NL - Nizozemsko
Klíč. slova	muscarinic acetylcholine receptors ; membrane cholesterol ; xanomeline ; receptor activation ; molecular dynamics
Vědní obor RIV	ED - Fyziologie
Obor OECD	Physiology (including cytology)
CEP	GA14-05696S GA ČR - Grantová agentura ČR
	GA17-16182S GA ČR - Grantová agentura ČR
Institucionální podpora	FGU-C - RVO:67985823
UT WOS	000429891800012
EID SCOPUS	85041673319
DOI	10.1016/j.neuropharm.2018.01.027
Anotace	Xanomeline (3-(Hexyloxy)-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole) is a muscarinic agonist that is considered to be functionally selective for the M1/M4 receptor subtypes. Part of xanomeline binding is resistant to washing. Wash-resistant xanomeline activates muscarinic receptors persistently, except for the M5 subtype. Mutation of leucine 6.46 to isoleucine at M1 or M4 receptors abolished persistent activation by wash-resistant xanomeline. Reciprocal mutation of isoleucine 6.46 to leucine at the M5 receptor made it sensitive to activation by wash-resistant xanomeline. Lowering of membrane cholesterol made M1 and M4 mutants and M5 wild type receptors sensitive to activation by wash-resistant xanomeline. Molecular docking revealed a cholesterol binding site in the groove between transmembrane helices 6 and 7. Molecular dynamics showed that interaction of cholesterol with this binding site attenuates receptor activation. We hypothesize that differences in cholesterol binding to this site between muscarinic receptor subtypes may constitute the basis for xanomeline apparent functional selectivity and may have notable therapeutic implications. Differences in receptor-membrane interactions, rather than in agonist-receptor interactions, represent a novel possibility to achieve pharmacological selectivity. Our findings may be applicable to other G protein coupled receptors.
Pracoviště	Fyziologický ústav
Kontakt	Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400
Rok sběru	2019

Počet záznamů: 1