神经NO合酶适配蛋白在代谢综合征和2型糖尿病发病中的作用

Q4 Biochemistry, Genetics and Molecular Biology Sibirskii nauchnyi meditsinskii zhurnal Pub Date : 2023-10-27 DOI:10.18699/ssmj20230504
L. A. Kuznetsova, N. E. Basova
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引用次数: 0

摘要

代谢综合征(MS)的发病机制以肥胖、高血压、血脂异常和胰岛素抵抗为特征。多发性硬化症增加患2型糖尿病(DM2)的风险。一氧化氮合酶(nNOS)的神经元异构体是由复杂的蛋白质-蛋白质相互作用定义的,因为与其他一氧化氮合酶异构体不同,nNOS含有一个c端PDZ结构域,这使得它可以与其他蛋白质结合,首先,与神经元或1型一氧化氮合酶(NOS1AP)的适配器相互作用,在我们的工作中也称为CAPON。nNOS与NOS1AP相互作用的改变导致脑、心、肝和骨骼肌代谢紊乱,在MS和T2DM的发生发展中起关键作用。NOS1AP与nNOS的PDZ结构域相互作用,与突触后密度蛋白(PSD95)竞争,调控nNOS亚细胞定位的稳定性和突触形成过程中酶的表达。NOS1AP促进nNOS与小GTPase (Dexras1)、突触嘧啶等靶标结合,调节树突根的形成,在兴奋毒性过程中介导nNOS- p38map激酶途径的激活。已有研究表明,NOS1AP基因的单核苷酸多态性及其在心肌中的过表达可导致长QT综合征的出现,在老年DM2患者中表现最为明显。我们发现NOS1AP基因多态性在使用钙阻滞剂时影响胰岛素分泌,并能促进DM2的发展。发现了NOS1AP在稳定骨骼肌nNOS与肌营养不良蛋白/肌营养不良蛋白相关的细胞骨架复合物中的功能中的功能作用。本综述的目的是提供NOS1AP和nNOS/NOS1AP复合物在MS和DM2发病机制中的作用的最新信息。讨论了NOS1AP与nNOS及其他蛋白相互作用导致nNOS活性、定位和含量变化的潜在分子机制。
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The role of the neural NO synthase adapter protein in the pathogenesis of metabolic syndrome and type 2 diabetes mellitus
The pathogenesis of metabolic syndrome (MS) is characterized by obesity, hypertension, dyslipidemia and insulin resistance. MS increases the risk of developing type 2 diabetes mellitus (DM2). The neuronal isoform of nitric oxide synthase (nNOS) is defined by complex protein-protein interactions, since nNOS, unlike other isoforms of NOS,contains a C-terminal PDZ domain, which allows it to conjugate with other proteins and, first of all, to interact with an adapter of neuronal, or type 1, nitric oxide synthase (NOS1AP), also denoted CAPON in our work. Changes in the interaction between nNOS and NOS1AP lead to metabolic disorders in brain, heart, liver and skeletal muscles, which plays a key role in the development of MS and T2DM. NOS1AP, interacting with the PDZ domain of nNOS, competes with the postsynaptic density protein (PSD95) and regulates the stability of subcellular localization of nNOS and enzyme expression during synapse formation. NOS1AP promotes nNOS binding to targets such as small GTPase (Dexras1), synapsines, regulating the formation of dendritic roots, mediates activation of the nNOS-p38MAP kinase pathway during excitotoxicity. It has been shown that single-nucleotide polymorphism of the NOS1AP gene and its overexpression in the myocardium leads to the manifestation of long QT syndrome, which is most clearly manifested in elderly patients with DM2. It was found that the genetic polymorphism of NOS1AP affects insulin secretion when using calcium blockers, and can promote the development of DM2. The functional role of NOS1AP in stabilizing the functions of skeletal muscle nNOS in the cytoskeletal complex associated with dystrophin/utrophin was discovered. The purpose of the review is to provide updated information on the role of NOS1AP and the nNOS/NOS1AP complex in the pathogenesis of MS and DM2. The potential molecular mechanisms of the interaction of NOS1AP with nNOS and with other proteins, which leads to change in nNOS activity, localization and content, are discussed.
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发文量
54
审稿时长
12 weeks
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