自然界最強の毒素の一つパリトキシンの作用機構を解明～パリトキシンはどのようにしてナトリウム・カリウムポンプを陽イオンチャネルに変えるか～

2025-09-18

2025-09-17 東京大学定量生命科学研究所

東京大学定量生命科学研究所の研究チームは、自然界最強の毒素の一つとされるパリトキシンが、神経興奮に必須のナトリウム・カリウムポンプを「陽イオンチャネル」に変える仕組みをクライオ電子顕微鏡で解明した。ポンプは本来、Na⁺とK⁺を濃度勾配に逆らって運ぶ二重ゲート機構を持つが、パリトキシンが結合すると両ゲートが同時に開き、Na⁺に限らず多様な陽イオンが自由に通過できる異常チャネルとなる。これにより細胞に過剰なNa⁺が流入し、興奮性異常や細胞死を引き起こす。今回の成果は、長年未解明だったポンプとチャネルの本質的違いを明らかにすると同時に、毎年報告されるパリトキシン様毒による食中毒の解毒剤開発に繋がると期待される。本研究は構造生物学の重要な進展である。

図1:ナトリウムカリウムポンプにパリトキシンが結合しチャネル化する様子
クライオ電子顕微鏡によって決定した三つの立体構造。紫の網は水が入れる空間を示す。

<関連情報>

パリトキシンがNa⁺,K⁺ポンプを陽イオンチャネルへ変換する仕組み How palytoxin transforms the Na+,K+ pump into a cation channel

Ryuta Kanai , Naoki Tsunekawa, Flemming Cornelius
Proceedings of the National Academy of Sciences Published:September 16, 2025
DOI:https://doi.org/10.1073/pnas.2506450122

Significance

Ion pumps transport ions across the membrane against their electrochemical gradients, utilizing free energy liberated by ATP hydrolysis. It has long been known that palytoxin, a potent marine toxin, transforms the Na⁺, K⁺ pump into a nonselective cation channel, suggesting that ion pumps and channels are alike. Indeed, ion pumping has been explained using a scheme that features two gates on either side of a membrane-traversing pore. The structures of the Na⁺, K⁺ pump with bound palytoxin presented here highlight that the architecture and operational principle of this representative ion pump are distinct from the “pore with two gates.” Notably, only one-half of the ion pathway exists at any time, preventing the formation of a continuous pore traversing the membrane.

Abstract

Palytoxin (PTX), a potent marine toxin, has long been known to transform Na⁺,K⁺-ATPase (NKA), an indispensable ion pump, into a nonselective cation channel. It has been postulated that PTX takes control of the two gates on either side of a channel-like pore. These gates normally open and close alternately, synchronized with chemical events, never opening simultaneously. A critical question is whether palytoxin takes over the control of the two gates or creates a new pathway. Here, we present structures of NKA with bound palytoxin in three different states. PTX binds to NKA in E2P, occupying the physiological Na⁺ exit pathway, similar to istaroxime, a new-generation cardiotonic steroid. Adding Na⁺ and ATP/ADP to the NKA·PTX complex induces an open channel traversing the entire membrane alongside the physiological ion pathway. As AlF_x, a stable transition state analog of phosphate replaces phosphate in the NKA·PTX complex preformed in E2P, the complex appears to undergo the normal reaction cycle from E2P to E1·nNa⁺. PTX occupies the space between the transmembrane helices M4 and M6, thereby preventing the closure of the extracellular half of the ion pathway. These structures demonstrate that the architecture of NKA is fundamentally different from “a pore with two gates.” Each half of the ion pathway comprises three segments, including a movable component that plays a pivotal role in translocating the bound cations by connecting the constant part to an appropriate inlet. The ion pathway of NKA transforms dynamically, ensuring that the two halves never exist simultaneously.