LY2087101 and dFBr share transmembrane binding sites in the (α4)3(β2)2 Nicotinic Acetylcholine Receptor

Abstract Positive allosteric modulators (PAMs) of nicotinic acetylcholine receptors (nAChRs) have potential therapeutic application in neuropathologies associated with decrease in function or loss of nAChRs. In this study, we characterize the pharmacological interactions of the nAChRs PAM, LY2087101...

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Autores principales:	Farah Deba, Hamed I. Ali, Abisola Tairu, Kara Ramos, Jihad Ali, Ayman K. Hamouda
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ea32213fb70144b6b14014e1daf21895
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spelling	oai:doaj.org-article:ea32213fb70144b6b14014e1daf218952021-12-02T15:08:28ZLY2087101 and dFBr share transmembrane binding sites in the (α4)3(β2)2 Nicotinic Acetylcholine Receptor10.1038/s41598-018-19790-42045-2322https://doaj.org/article/ea32213fb70144b6b14014e1daf218952018-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-19790-4https://doaj.org/toc/2045-2322Abstract Positive allosteric modulators (PAMs) of nicotinic acetylcholine receptors (nAChRs) have potential therapeutic application in neuropathologies associated with decrease in function or loss of nAChRs. In this study, we characterize the pharmacological interactions of the nAChRs PAM, LY2087101, with the α4β2 nAChR using mutational and computational analyses. LY2087101 potentiated ACh-induced currents of low-sensitivity (α4)3(β2)2 and high-sensitivity (α4)2(β2)3 nAChRs with similar potencies albeit to a different maximum potentiation (potentiation I max = ~840 and 450%, respectively). Amino acid substitutions within the α4 subunit transmembrane domain [e.g. α4Leu256 and α4Leu260 within the transmembrane helix 1 (TM1); α4Phe316 within the TM3; and α4Gly613 within TM4] significantly reduced LY2087101 potentiation of (α4)3(β2)2 nAChR. The locations of these amino acid residues and LY2087101 computational docking analyses identify two LY2087101 binding sites: an intrasubunit binding site within the transmembrane helix bundle of α4 subunit at the level of α4Leu260/α4Phe316 and intersubunit binding site at the α4:α4 subunit interface at the level of α4Leu256/α4Ile315 with both sites extending toward the extracellular end of the transmembrane domain. We also show that desformylflustrabromine (dFBr) binds to these two sites identified for LY2087101. These results provide structural information that are pertinent to structure-based design of nAChR allosteric modulators.Farah DebaHamed I. AliAbisola TairuKara RamosJihad AliAyman K. HamoudaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-18 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Farah Deba Hamed I. Ali Abisola Tairu Kara Ramos Jihad Ali Ayman K. Hamouda LY2087101 and dFBr share transmembrane binding sites in the (α4)3(β2)2 Nicotinic Acetylcholine Receptor
description	Abstract Positive allosteric modulators (PAMs) of nicotinic acetylcholine receptors (nAChRs) have potential therapeutic application in neuropathologies associated with decrease in function or loss of nAChRs. In this study, we characterize the pharmacological interactions of the nAChRs PAM, LY2087101, with the α4β2 nAChR using mutational and computational analyses. LY2087101 potentiated ACh-induced currents of low-sensitivity (α4)3(β2)2 and high-sensitivity (α4)2(β2)3 nAChRs with similar potencies albeit to a different maximum potentiation (potentiation I max = ~840 and 450%, respectively). Amino acid substitutions within the α4 subunit transmembrane domain [e.g. α4Leu256 and α4Leu260 within the transmembrane helix 1 (TM1); α4Phe316 within the TM3; and α4Gly613 within TM4] significantly reduced LY2087101 potentiation of (α4)3(β2)2 nAChR. The locations of these amino acid residues and LY2087101 computational docking analyses identify two LY2087101 binding sites: an intrasubunit binding site within the transmembrane helix bundle of α4 subunit at the level of α4Leu260/α4Phe316 and intersubunit binding site at the α4:α4 subunit interface at the level of α4Leu256/α4Ile315 with both sites extending toward the extracellular end of the transmembrane domain. We also show that desformylflustrabromine (dFBr) binds to these two sites identified for LY2087101. These results provide structural information that are pertinent to structure-based design of nAChR allosteric modulators.
format	article
author	Farah Deba Hamed I. Ali Abisola Tairu Kara Ramos Jihad Ali Ayman K. Hamouda
author_facet	Farah Deba Hamed I. Ali Abisola Tairu Kara Ramos Jihad Ali Ayman K. Hamouda
author_sort	Farah Deba
title	LY2087101 and dFBr share transmembrane binding sites in the (α4)3(β2)2 Nicotinic Acetylcholine Receptor
title_short	LY2087101 and dFBr share transmembrane binding sites in the (α4)3(β2)2 Nicotinic Acetylcholine Receptor
title_full	LY2087101 and dFBr share transmembrane binding sites in the (α4)3(β2)2 Nicotinic Acetylcholine Receptor
title_fullStr	LY2087101 and dFBr share transmembrane binding sites in the (α4)3(β2)2 Nicotinic Acetylcholine Receptor
title_full_unstemmed	LY2087101 and dFBr share transmembrane binding sites in the (α4)3(β2)2 Nicotinic Acetylcholine Receptor
title_sort	ly2087101 and dfbr share transmembrane binding sites in the (α4)3(β2)2 nicotinic acetylcholine receptor
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/ea32213fb70144b6b14014e1daf21895
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LY2087101 and dFBr share transmembrane binding sites in the (α4)3(β2)2 Nicotinic Acetylcholine Receptor

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