Species specificity of rat and human α7 nicotinic acetylcholine receptors towards different classes of peptide and protein antagonists
Yu J., Zhu X., Zhang L., Kudryavtsev D., Kasheverov I. E., Lei Y., Zhangsun D., Tsetlin V., Luo S.
Neuropharmacology
Vol.139, P. 226-237
Опубликовано: 2018
Тип ресурса: Статья
DOI:10.1016/j.neuropharm.2018.07.019
Аннотация:
Peptide and protein neurotoxins, such as α-conotoxins from Cone snails and α-neurotoxins from snake venoms, are excellent tools to identify distinct nicotinic acetylcholine receptor (nAChR) subtypes. Here we compared the rat/human species specificity of α7 nAChR towards peptide and protein neurotoxins and found that α-conotoxin analogues [K11A]TxIB and [H5D]RegIIA are much more potent on the rat versus human α7 receptor expressed in Xenopus oocytes. In the hope to determine the key residue responsible for the difference in α-conotoxin analogues affinities, ten single mutants of rat α7 nAChR were obtained because there are 10 differences in the extracellular ligand-binding domains of these species, and only K185R mutation decreased the affinity for α-conotoxins [K11A]TxIB and [H5D]RegIIA, down to their low affinities for human α7 nAChR. On the other hand, the reverse mutation R185K in human α7 nAChR resulted in the greatest increase in the affinity for both conotoxins, while a double mu
Ключевые слова:
Ligand binding domain; Point mutations; Sequence difference; Xenopus oocytes; α-Cobratoxin; α-Conotoxins; α7 nAChR
alpha conotoxin derivative; bungarotoxin receptor; extracellular ligand binding domain protein; lysine; mutant protein; neurotoxin derivative; protein derivative; unclassified drug; bungarotoxin receptor; chlorisondamine; conotoxin; nicotinic receptor blocking agent; protein binding; Article; binding affinity; computer model; controlled study; dose response; drug design; drug potency; drug receptor binding; EC50; evoked response; human; molecular model; mutational analysis; nonhuman; oocyte; priority journal; protein expression; rat; species difference; Xenopus; amino acid sequence; animal; antagonists and inhibitors; comparative study; drug effect; genetic transfection; genetics; hydrogen bond; membrane potential; metabolism; molecular dynamics; physiology; site directed mutagenesis; species difference; alpha7 Nicotinic Acetylcholine Receptor; Amino Acid Sequence; Animals; Chlorisondamine; Conotoxins; Dose-Response Relationship, Drug; Humans; Hydrogen Bonding; Membrane Potentials; Mol
Язык текста: Английский
ISSN: 1873-7064
Yu J.
Zhu X.
Zhang L.
Kudryavtsev D.
Kasheverov I. E. Igor` Evgenyevich 1966-
Lei Y.
Zhangsun D.
Tsetlin V.
Luo S.
Й.
Жу Х.
Жанг Л.
Кудрявцев Д.
Кашеверов И. Е. Игорь Евгеньевич 1966-
Леи Y.
Жангсун Д.
Цетлин В.
Луо С.
Species specificity of rat and human α7 nicotinic acetylcholine receptors towards different classes of peptide and protein antagonists
Текст визуальный непосредственный
Neuropharmacology
Elsevier Science Publisher B.V.
Vol.139 P. 226-237
2018
Статья
Ligand binding domain Point mutations Sequence difference Xenopus oocytes α-Cobratoxin α-Conotoxins α7 nAChR
alpha conotoxin derivative bungarotoxin receptor extracellular ligand binding domain protein lysine mutant protein neurotoxin derivative protein derivative unclassified drug bungarotoxin receptor chlorisondamine conotoxin nicotinic receptor blocking agent protein binding Article binding affinity computer model controlled study dose response drug design drug potency drug receptor binding EC50 evoked response human molecular model mutational analysis nonhuman oocyte priority journal protein expression rat species difference Xenopus amino acid sequence animal antagonists and inhibitors comparative study drug effect genetic transfection genetics hydrogen bond membrane potential metabolism molecular dynamics physiology site directed mutagenesis species difference alpha7 Nicotinic Acetylcholine Receptor Amino Acid Sequence Animals Chlorisondamine Conotoxins Dose-Response Relationship, Drug Humans Hydrogen Bonding Membrane Potentials Mol
Peptide and protein neurotoxins, such as α-conotoxins from Cone snails and α-neurotoxins from snake venoms, are excellent tools to identify distinct nicotinic acetylcholine receptor (nAChR) subtypes. Here we compared the rat/human species specificity of α7 nAChR towards peptide and protein neurotoxins and found that α-conotoxin analogues [K11A]TxIB and [H5D]RegIIA are much more potent on the rat versus human α7 receptor expressed in Xenopus oocytes. In the hope to determine the key residue responsible for the difference in α-conotoxin analogues affinities, ten single mutants of rat α7 nAChR were obtained because there are 10 differences in the extracellular ligand-binding domains of these species, and only K185R mutation decreased the affinity for α-conotoxins [K11A]TxIB and [H5D]RegIIA, down to their low affinities for human α7 nAChR. On the other hand, the reverse mutation R185K in human α7 nAChR resulted in the greatest increase in the affinity for both conotoxins, while a double mu