摘要
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。
Ligand-gated ion channels are a large category of essential ion channels,modulating their state by binding to specific ligands to allow ions to pass through the cell membrane.Purinergic ligand-gated ion channel receptors(P2XRs)and acid-sensitive ion channels(ASICs)are representative members of trimeric ligand-gated ion channel.Recent studies have shown that structural differences in the intracellular domain of P2XRs may determine the desensitization process.The lateral fenestrations of P2XRs potentially serve as a pathway for ion conductance and play a decisive role in ion selectivity.Phosphorylation of numerous amino acid residues in the P2XRs are involved in regulating the activity of ion channels.Additionally,the P2XRs interact with other ligand-gated ion channels including N-methyl-D-aspartate receptors,γ-aminobutyric acid receptors,5-hydroxytryptamin receptors and nicotinic acetylcholine receptors,mediating physiological processes such as synaptic plasticity.Conformational changes in the intracellular domain of the ASICs expose binding sites of intracellular signal partners,facilitating metabolic signal transduction.Amino acids such as Val16,Ser17,Ile18,Gln19 and Ala20 in the ASICs participate in channel opening and membrane expression.ASICs can also bind to intracellular proteins,such as CIPP and p11,to regulate channel function.Many phosphorylation sites at the C-terminus and N-terminus of ASICs are involved in the regulation of receptors.Furthermore,ASICs are involved in various physiological and pathophysiological processes,which include pain,ischemic stroke,psychiatric disorders,and neurodegenerative disease.In this article,we review the roles of the intracellular domains of these trimeric ligand�gated ion channels in channel gating as well as their physiological and pathological functions,in order to provide new insights into the discovery of related drugs.
作者
鲁燕
林义雨
汪津
LU Yan;LIN Yiyu;WANG Jin(School of Basic Medicine and Clinical Pharmacy,China Pharmaceutical University,Nanjing 210009,China)
出处
《浙江大学学报（医学版）》
CAS
CSCD
北大核心
2024年第2期221-230,共10页
Journal of Zhejiang University(Medical Sciences)
基金
国家自然科学基金(32000869)。
关键词
三聚体配体门控离子通道
胞内区域
门控
功能
综述
Function Trimeric ligand-gated ion channels
Intracellular domain
Gating
Review
