Oligoarginine peptides, a new family of nicotinic acetylcholine receptor inhibitors
Lebedev D. S., Kryukova E. V., Ivanov I. A., Egorova N. S., Timofeev N. D., Spirova E. N., Tufanova E. Y., Siniavin A. E., Kudryavtsev D. S., Kasheverov I. E., Zouridakis M., Katsarava R., Zavradashvili N., Iagorshvili I., Tzartos S. J., Tsetlin V. I.
Molecular Pharmacology
Vol.96, Issue5, P. 664-673
Опубликовано: 2019
Тип ресурса: Статья
DOI:10.1124/mol.119.117713
Аннотация:
Many peptide ligands of nicotinic acetylcholine receptors (nAChRs) contain a large number of positively charged amino acid residues, a striking example being conotoxins RgIA and GeXIVA from marine mollusk venom, with an arginine content of .30[%]. To determine whether peptides built exclusively from arginine residues will interact with different nAChR subtypes or with their structural homologs such as the acetylcholine-binding protein and ligand-binding domain of the nAChR a9 subunit, we synthesized a series of R3, R6, R8, and R16 oligoarginines and investigated their activity by competition with radioiodinated a-bungarotoxin, two-electrode voltage-clamp electrophysiology, and calcium imaging. R6 and longer peptides inhibited muscle-type nAChRs, a7 nAChRs, and a3b2 nAChRs in the micromolar range. The most efficient inhibition of ion currents was detected for muscle nAChR by R16 (IC50 5 157 nM) and for the a9a10 subtype by R8 and R16 (IC50 5 44 and 120 nM, respectively). Since the R8 affi
Ключевые слова:
alpha bungarotoxin; bungarotoxin receptor; calcium; cell penetrating peptide; nicotinic receptor; nicotinic receptor alpha3beta2; nicotinic receptor alpha9beta10; nicotinic receptor blocking agent; oligoarginine peptide; oligomer; peptide; tryptophan; unclassified drug; arginine; nicotinic receptor; nicotinic receptor blocking agent; peptide; animal experiment; Article; binding affinity; binding site; biological activity; controlled study; drug delivery system; electrophysiology; human; human cell; ion current; ligand binding; mouse; muscle; nonhuman; peptide synthesis; priority journal; radioiodination; voltage clamp technique; animal; chemistry; dose response; female; metabolism; tumor cell line; Xenopus laevis; Animals; Arginine; Cell Line, Tumor; Dose-Response Relationship, Drug; Female; Humans; Mice; Nicotinic Antagonists; Peptides; Receptors, Nicotinic; Xenopus laevis
Язык текста: Английский
ISSN: 1521-0111
Lebedev D. S.
Kryukova E. V.
Ivanov I. A.
Egorova N. S.
Timofeev N. D.
Spirova E. N.
Tufanova E. Y. E.Yu.
Siniavin A. E.
Kudryavtsev D. S.
Kasheverov I. E. Igor` Evgenyevich 1966-
Zouridakis M.
Katsarava R.
Zavradashvili N.
Iagorshvili I.
Tzartos S. J.
Tsetlin V. I.
Лебедев Д. С.
Крюкова Е. В.
Иванов И. А.
Егорова Н. С.
Тимофеев Н. Д.
Спирова Е. Н.
Тюфанова Е. Y. Е.Ю.
Синиавин А. Е.
Кудрявцев Д. С.
Кашеверов И. Е. Игорь Евгеньевич 1966-
Зоуридакис М.
Кацарава Р.
Заврадашвили Н.
Иагоршвили И.
Тзартос С. Й.
Цетлин В. И.
Oligoarginine peptides, a new family of nicotinic acetylcholine receptor inhibitors
Текст визуальный непосредственный
Molecular Pharmacology
American Society for Pharmacology and Experimental Therapeutics
Vol.96, Issue5 P. 664-673
2019
Статья
alpha bungarotoxin bungarotoxin receptor calcium cell penetrating peptide nicotinic receptor nicotinic receptor alpha3beta2 nicotinic receptor alpha9beta10 nicotinic receptor blocking agent oligoarginine peptide oligomer peptide tryptophan unclassified drug arginine nicotinic receptor nicotinic receptor blocking agent peptide animal experiment Article binding affinity binding site biological activity controlled study drug delivery system electrophysiology human human cell ion current ligand binding mouse muscle nonhuman peptide synthesis priority journal radioiodination voltage clamp technique animal chemistry dose response female metabolism tumor cell line Xenopus laevis Animals Arginine Cell Line, Tumor Dose-Response Relationship, Drug Female Humans Mice Nicotinic Antagonists Peptides Receptors, Nicotinic Xenopus laevis
Many peptide ligands of nicotinic acetylcholine receptors (nAChRs) contain a large number of positively charged amino acid residues, a striking example being conotoxins RgIA and GeXIVA from marine mollusk venom, with an arginine content of .30[%]. To determine whether peptides built exclusively from arginine residues will interact with different nAChR subtypes or with their structural homologs such as the acetylcholine-binding protein and ligand-binding domain of the nAChR a9 subunit, we synthesized a series of R3, R6, R8, and R16 oligoarginines and investigated their activity by competition with radioiodinated a-bungarotoxin, two-electrode voltage-clamp electrophysiology, and calcium imaging. R6 and longer peptides inhibited muscle-type nAChRs, a7 nAChRs, and a3b2 nAChRs in the micromolar range. The most efficient inhibition of ion currents was detected for muscle nAChR by R16 (IC50 5 157 nM) and for the a9a10 subtype by R8 and R16 (IC50 5 44 and 120 nM, respectively). Since the R8 affi