| Item type |
デフォルトアイテムタイプ_（フル）(1) |
| 公開日 |
2023-03-18 |
| タイトル |
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|
タイトル |
Distinct sites regulating grayanotoxin binding and unbinding to D4S6 of Nav1.4 sodium channel as revealed by improved estimation of toxin sensitivity |
|
言語 |
en |
| 作成者 |
Maejima, Hiroshi
Kinoshita, Eiji
Seyama, Issei
Yamaoka, Kaoru
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| アクセス権 |
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アクセス権 |
open access |
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アクセス権URI |
http://purl.org/coar/access_right/c_abf2 |
| 権利情報 |
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|
権利情報 |
Copyright (c) 2003 by the American Society for Biochemistry and Molecular Biology. |
| 主題 |
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主題Scheme |
NDC |
|
主題 |
460 |
| 内容記述 |
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内容記述 |
Grayanotoxin (GTX) exerts selective effects on voltage-dependent sodium channels by eliminating fast sodium inactivation and causing a hyperpolarizing shift in voltagedependency of channel activation. In this study, we adopted a newly developed protocol that provides independent estimates of the binding and unbinding rate constants of GTX (kon and koff) to GTX-sites on the sodium channel protein, important in the molecular analysis of channel modification. Novel GTX-sites were determined in D2S6 (N784) and D3S6 (S1276) by means of site-directed mutagenesis; the results suggested that the GTX receptor consists of the S6 transmembrane segments of four quasi-homologous domains facing the ionconducting pore. We systematically introduced at two sites in D4S6 (Nav1.4-F1579 and Nav1.4-Y1586) amino acid substituents with residues containing hydrophobic, aromatic, charged, or polar groups. Generally, substitutions at F1579 increased both kon and koff, resulting in no prominent change in dissociation constant (Kd). It seems that the smaller the molecular size of the residue at Nav1.4-F1579, the larger the rates of kon and koff, indicating that this site acts as a gate regulating access of toxin molecules to a receptor site. Substitutions at Y1586 selectively increased koff but had virtually no effect on kon, thus causing a drastic increase in Kd. At position Y1586, a hydrophobic or aromatic amino acid side chain was required to maintain normal sensitivity to GTX. These results suggest that the residue at position Y1586 has a more critical role in mediating GTX binding than the one at position F1579. Here, we propose that the affinity of GTX to Nav1.4 sodium channels might be regulated by two residues (Phe and Tyr) at positions F1579 and Y1586, which respectively control access and binding of GTX to its receptor. |
|
言語 |
en |
| 出版者 |
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|
出版者 |
The American Society for Biochemistry and Molecular Biology |
| 言語 |
|
|
言語 |
eng |
| 資源タイプ |
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資源タイプ識別子 |
http://purl.org/coar/resource_type/c_6501 |
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資源タイプ |
journal article |
| 出版タイプ |
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|
出版タイプ |
AO |
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出版タイプResource |
http://purl.org/coar/version/c_b1a7d7d4d402bcce |
| 関連情報 |
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識別子タイプ |
DOI |
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関連識別子 |
10.1074/jbc.M212133200 |
| 関連情報 |
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|
識別子タイプ |
PMID |
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関連識別子 |
12524436 |
| 関連情報 |
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|
関連タイプ |
isVersionOf |
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|
識別子タイプ |
DOI |
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|
関連識別子 |
http://dx.doi.org/10.1074/jbc.M212133200 |
| 収録物識別子 |
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収録物識別子タイプ |
ISSN |
|
収録物識別子 |
0021-9258 |
| 収録物識別子 |
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収録物識別子タイプ |
NCID |
|
収録物識別子 |
AA00251083 |
| 開始ページ |
|
|
開始ページ |
9464 |
| 書誌情報 |
The journal of biological chemistry
The journal of biological chemistry
巻 278,
号 11,
p. 9464-9471,
発行日 2003-03-14
|
| 旧ID |
17133 |
JBC_278_9464.pdf (904.0 KB)
