FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2894521979> ?p ?o ?g. }

• W2894521979 endingPage "17852" @default.
• W2894521979 startingPage "17838" @default.
• W2894521979 abstract "Nicotinic acetylcholine receptors (nAChRs) containing α6 and β4 subunits are expressed by dorsal root ganglion neurons and have been implicated in neuropathic pain. Rodent models are often used to evaluate the efficacy of analgesic compounds, but species differences may affect the activity of some nAChR ligands. A previous candidate α-conotoxin-based therapeutic yielded promising results in rodent models, but failed in human clinical trials, emphasizing the importance of understanding species differences in ligand activity. Here, we show that human and rat α6/α3β4 nAChRs expressed in Xenopus laevis oocytes exhibit differential sensitivity to α-conotoxins. Sequence homology comparisons of human and rat α6β4 nAChR subunits indicated that α6 residues forming the ligand-binding pocket are highly conserved between the two species, but several residues of β4 differed, including a Leu–Gln difference at position 119. X-ray crystallography of α-conotoxin PeIA complexed with the Aplysia californica acetylcholine-binding protein (AChBP) revealed that binding of PeIA orients Pro13 in close proximity to residue 119 of the AChBP complementary subunit. Site-directed mutagenesis studies revealed that Leu119 of human β4 contributes to higher sensitivity of human α6/α3β4 nAChRs to α-conotoxins, and structure–activity studies indicated that PeIA Pro13 is critical for high potency. Human and rat α6/α3β4 nAChRs displayed differential sensitivities to perturbations of the interaction between PeIA Pro13 and residue 119 of the β4 subunit. These results highlight the potential significance of species differences in α6β4 nAChR pharmacology that should be taken into consideration when evaluating the activity of candidate human therapeutics in rodent models. Nicotinic acetylcholine receptors (nAChRs) containing α6 and β4 subunits are expressed by dorsal root ganglion neurons and have been implicated in neuropathic pain. Rodent models are often used to evaluate the efficacy of analgesic compounds, but species differences may affect the activity of some nAChR ligands. A previous candidate α-conotoxin-based therapeutic yielded promising results in rodent models, but failed in human clinical trials, emphasizing the importance of understanding species differences in ligand activity. Here, we show that human and rat α6/α3β4 nAChRs expressed in Xenopus laevis oocytes exhibit differential sensitivity to α-conotoxins. Sequence homology comparisons of human and rat α6β4 nAChR subunits indicated that α6 residues forming the ligand-binding pocket are highly conserved between the two species, but several residues of β4 differed, including a Leu–Gln difference at position 119. X-ray crystallography of α-conotoxin PeIA complexed with the Aplysia californica acetylcholine-binding protein (AChBP) revealed that binding of PeIA orients Pro13 in close proximity to residue 119 of the AChBP complementary subunit. Site-directed mutagenesis studies revealed that Leu119 of human β4 contributes to higher sensitivity of human α6/α3β4 nAChRs to α-conotoxins, and structure–activity studies indicated that PeIA Pro13 is critical for high potency. Human and rat α6/α3β4 nAChRs displayed differential sensitivities to perturbations of the interaction between PeIA Pro13 and residue 119 of the β4 subunit. These results highlight the potential significance of species differences in α6β4 nAChR pharmacology that should be taken into consideration when evaluating the activity of candidate human therapeutics in rodent models." @default.
• W2894521979 created "2018-10-05" @default.
• W2894521979 creator A5013807736 @default.
• W2894521979 creator A5015410355 @default.
• W2894521979 creator A5015525492 @default.
• W2894521979 creator A5032974804 @default.
• W2894521979 creator A5050848441 @default.
• W2894521979 creator A5055317480 @default.
• W2894521979 creator A5061587018 @default.
• W2894521979 creator A5062659375 @default.
• W2894521979 creator A5072414465 @default.
• W2894521979 creator A5086864255 @default.
• W2894521979 date "2018-11-01" @default.
• W2894521979 modified "2023-10-17" @default.
• W2894521979 title "Molecular determinants of α-conotoxin potency for inhibition of human and rat α6β4 nicotinic acetylcholine receptors" @default.
• W2894521979 cites W1504555080 @default.
• W2894521979 cites W1515685619 @default.
• W2894521979 cites W1539796472 @default.
• W2894521979 cites W1560891849 @default.
• W2894521979 cites W1637250296 @default.
• W2894521979 cites W1829037758 @default.
• W2894521979 cites W1917275022 @default.
• W2894521979 cites W1928871450 @default.
• W2894521979 cites W1970119464 @default.
• W2894521979 cites W1970469302 @default.
• W2894521979 cites W198782672 @default.
• W2894521979 cites W1988072680 @default.
• W2894521979 cites W1990787844 @default.
• W2894521979 cites W1992242607 @default.
• W2894521979 cites W1996933707 @default.
• W2894521979 cites W2009809547 @default.
• W2894521979 cites W2009828274 @default.
• W2894521979 cites W2016687933 @default.
• W2894521979 cites W2016765195 @default.
• W2894521979 cites W2023551620 @default.
• W2894521979 cites W2030508076 @default.
• W2894521979 cites W2041720100 @default.
• W2894521979 cites W2044907489 @default.
• W2894521979 cites W2051648601 @default.
• W2894521979 cites W2052745304 @default.
• W2894521979 cites W2053870022 @default.
• W2894521979 cites W2059235702 @default.
• W2894521979 cites W2062473403 @default.
• W2894521979 cites W2074655805 @default.
• W2894521979 cites W2085405019 @default.
• W2894521979 cites W2087199848 @default.
• W2894521979 cites W2089819387 @default.
• W2894521979 cites W2094671349 @default.
• W2894521979 cites W2097345469 @default.
• W2894521979 cites W2099277573 @default.
• W2894521979 cites W2104838343 @default.
• W2894521979 cites W2111150014 @default.
• W2894521979 cites W2112418305 @default.
• W2894521979 cites W2115872169 @default.
• W2894521979 cites W2126829020 @default.
• W2894521979 cites W2128779418 @default.
• W2894521979 cites W2135248571 @default.
• W2894521979 cites W2139437087 @default.
• W2894521979 cites W2141830709 @default.
• W2894521979 cites W2142101907 @default.
• W2894521979 cites W2144081223 @default.
• W2894521979 cites W2148677994 @default.
• W2894521979 cites W2154197653 @default.
• W2894521979 cites W2154714625 @default.
• W2894521979 cites W2155687897 @default.
• W2894521979 cites W2163545771 @default.
• W2894521979 cites W2169707043 @default.
• W2894521979 cites W2170194206 @default.
• W2894521979 cites W2531185175 @default.
• W2894521979 cites W2578823059 @default.
• W2894521979 cites W2610395588 @default.
• W2894521979 cites W2620568348 @default.
• W2894521979 cites W2752919082 @default.
• W2894521979 cites W2761215766 @default.
• W2894521979 cites W2772937150 @default.
• W2894521979 doi "https://doi.org/10.1074/jbc.ra118.005649" @default.
• W2894521979 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6240866" @default.
• W2894521979 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30249616" @default.
• W2894521979 hasPublicationYear "2018" @default.
• W2894521979 type Work @default.
• W2894521979 sameAs 2894521979 @default.
• W2894521979 citedByCount "18" @default.
• W2894521979 countsByYear W28945219792019 @default.
• W2894521979 countsByYear W28945219792020 @default.
• W2894521979 countsByYear W28945219792021 @default.
• W2894521979 countsByYear W28945219792022 @default.
• W2894521979 countsByYear W28945219792023 @default.
• W2894521979 crossrefType "journal-article" @default.
• W2894521979 hasAuthorship W2894521979A5013807736 @default.
• W2894521979 hasAuthorship W2894521979A5015410355 @default.
• W2894521979 hasAuthorship W2894521979A5015525492 @default.
• W2894521979 hasAuthorship W2894521979A5032974804 @default.
• W2894521979 hasAuthorship W2894521979A5050848441 @default.
• W2894521979 hasAuthorship W2894521979A5055317480 @default.
• W2894521979 hasAuthorship W2894521979A5061587018 @default.
• W2894521979 hasAuthorship W2894521979A5062659375 @default.
• W2894521979 hasAuthorship W2894521979A5072414465 @default.
• W2894521979 hasAuthorship W2894521979A5086864255 @default.

• next