Neurosteroids as positive and negative allosteric modulators of ligand-gated ion channels: P2X receptor perspective

Sivcev, Sonja; Kudová, Eva; Zemková, Hana

doi:10.1016/j.neuropharm.2023.109542

Cited by 6 publications

(1 citation statement)

References 194 publications

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“…配体门控离子通道根据所结合的配体可分为N型乙酰胆碱受体通道、谷氨酸受体通道和门冬氨酸受体通道等，这些通道由不同数量的亚基组装而成，形成三聚体配体门控离子通道、四聚体配体门控离子通道（谷氨酸阳离子受体超家族）和五聚体配体门控离子通道（半胱氨酸-环受体超家族）［ 8 ］。配体门控离子通道根据细胞膜的位置可以分为胞外区域、跨膜区以及胞内区域。不同亚基的胞外区域相互作用组成了通道的配体结合位点以及众多调节位点；不同亚基的跨膜区相互作用组成了通道的离子通透区域，在细胞膜上形成一个通道，允许特定类型的离子通过；胞内区域除了提供不同跨膜螺旋之间必要的连接之外，还往往与通道组装和上膜相关联。见图1 。…”

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Recent progress in understanding the intracellular domain's gating and functional roles in trimeric ligand-gated ion channels

LU,

LIN,

WANG

2024

J Zhejiang Univ (Med Sci)

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配体门控离子通道是一大类重要的膜蛋白。嘌呤能配体门控离子通道（P2X）受体和酸敏感离子通道（ASIC）是三聚体配体门控离子通道的代表成员。P2X受体胞内区域的结构差异可影响脱敏过程，胞内区域的侧窗可作为离子渗透到细胞内的潜在路径并对离子选择性有决定作用，胞内区域众多氨基酸残基的磷酸化参与调节离子通道的活性。此外，胞内区域与 N -甲基- D -天冬氨酸受体、γ-氨基丁酸受体、5-羟色胺受体和N型乙酰胆碱受体等其他配体门控离子通道存在相互作用并介导突触可塑性等病理生理过程。ASIC胞内区域的构象变化会暴露胞内信号分子的结合位点并促进代谢信号转导，胞内区域的氨基酸Val16、Ser17、Ile18、Gln19和Ala20可以调节通道上膜表达并参与门控过程，胞内区域的PDZ结构域可与多种细胞内蛋白质如骨架蛋白CIPP和p11相互作用从而参与对受体的调控，胞内区域羧基端和氨基端的众多磷酸化位点参与了对受体的调控。此外，胞内区域参与了疼痛、缺血性脑卒中、精神疾病、神经退行性疾病等多种病理生理过程。本文综述了P2X受体和ASIC胞内区域的结构以及在调节离子通道的门控特性和病理生理功能中的作用，以期为三聚体配体门控离子通道的药物研发提供新思路。

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Recent progress in understanding the intracellular domain's gating and functional roles in trimeric ligand-gated ion channels

LU,

LIN,

WANG

2024

J Zhejiang Univ (Med Sci)

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Monovalent cation binding to model systems and the macrocyclic depsipeptide, emodepside

Subramanian,

Manchanda,

et al. 2024

J Comput Chem

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This study focuses on the systematic exploration of the emodepside conformations bound to monovalent K+ ion using quantum mechanical density functional theory (DFT) calculations at the M06‐2X/6‐31+G(d,p) level of theory. Nine conformers of emodepside and their complexes with K+ ion were characterized as stationary points on the potential energy surface. The conformational isomers were examined for their 3D structures, bonding, energetics, and interactions with the cation. A cavitand‐like structure (CC) is identified to be the energetically most stable arrangement. To arrive at a better understanding of the K+ ion binding, calculations were initially performed on complexes formed by the K+ and Na+ ions with model ligands (methyl ester and N,N‐dimethyl acetamide). Both the natural bond orbital (NBO) method and the block‐localized wavefunction (BLW) energy decomposition approach was employed to assess the bonding and energetic contributions stabilizing the ion‐bound model complexes. Finally, the solvent effect was evaluated through complete geometry optimizations and energy minimizations for the model ion‐ligand complexes and the emodepside‐K+ bound complexes using an implicit solvent model mimicking water and DMSO.

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Is there a biochemical basis for purinergic P2X3 and P2X4 receptor antagonists to be considered as anti-seizure medications?

Witkin,

Shafique,

Smith

et al. 2024

Biochemical Pharmacology

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Neurosteroids as positive and negative allosteric modulators of ligand-gated ion channels: P2X receptor perspective

Cited by 6 publications

References 194 publications

Recent progress in understanding the intracellular domain's gating and functional roles in trimeric ligand-gated ion channels

Recent progress in understanding the intracellular domain's gating and functional roles in trimeric ligand-gated ion channels

Monovalent cation binding to model systems and the macrocyclic depsipeptide, emodepside

Is there a biochemical basis for purinergic P2X3 and P2X4 receptor antagonists to be considered as anti-seizure medications?

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