sibmedСибирский научный медицинский журналСибирский научный медицинский журнал2410-25122410-2520ИЦиГ СО РАН10.18699/SSMJ20230504sibmed-1236Research ArticleОБЗОРЫREVIEWSРоль адаптерного белка нейрональной NO-синтазы в патогенезе метаболического синдрома и сахарного диабета 2 типаThe role of the neural NO synthase adapter protein in the pathogenesis of metabolic syndrome and type 2 diabetes mellitushttps://orcid.org/0000-0001-9215-6018КузнецоваЛ. А.KuznetsovaL. A.

д.б.н.

194223, г. Санкт-Петербург, пр. Тореза, 44

doctor of biological sciences

194223, St. Petersburg, Thorezа ave., 44

praskovia1231@mail.ruhttps://orcid.org/0000-0002-7316-2882БасоваН. Е.BasovaN. E.

к.б.н.

194223, г. Санкт-Петербург, пр. Тореза, 44

candidate of biological sciences

194223, St. Petersburg, Thorezа ave., 44

basovnat@mail.ruИнститут эволюционной физиологии и биохимии им. И.М. Сеченова РАНРоссияSechenov Institute of Evolutionary Physiology and Biochemistry RASRussian Federation2023271020234353449Copyright © Кузнецова Л.А., Басова Н.Е., 20232023Кузнецова Л.А., Басова Н.Е.Kuznetsova L.A., Basova N.E.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://sibmed.elpub.ru/jour/article/view/1236

Патогенез метаболического синдрома (МС) характеризуется ожирением, гипертонией, дислипидемией и инсулинорезистентностью. МС увеличивает риск развития сахарного диабета 2-го типа (СД2). Для нейрональной изоформы синтазы оксида азота (nNOS) характерны сложные белок-белковые взаимодействия, так как nNOS, в отличие от других изоформ NOS, содержит C-концевой домен PDZ, позволяющий ей сопрягаться с другими белками. Для этого домена характерно взаимодействие с адаптерным белком, называемым в нашей работе адаптер нейрональной, или типа 1, синтазы оксида азота (NOS1AP), также обозначаемым как CAPON. Изменение взаимодействия между nNOS и NOS1AP приводит к нарушению метаболизма в мозге, сердце, печени и скелетных мышцах, что играет ключевую роль при развитии МС и СД2. NOS1AP, взаимодействуя c доменом PDZ nNOS, конкурирует с белком постсинаптической плотности (PSD95) и регулирует стабильность субклеточной локализации nNOS и экспрессию фермента при формированиия синапсов. NOS1AP способствует связыванию nNOS с такими мишенями, как малая ГТФаза (Dexras1) и синапсины, регулирует образование дендритных корешков, опосредует активацию пути «nNOS – p38MAP-киназа» при эксайтотоксичности. Показано, что однонуклеотидный полиморфизм гена NOS1AP или его избыточная экспрессия в миокарде приводит к проявлению синдрома удлиненного интервала QT, что проявляется у пожилых пациентов с СД2. Обнаружено, что полиморфизм гена NOS1AP влияет на секрецию инсулина при использовании блокаторов кальциевых каналов и может способствовать развитию СД2. Обнаружена функциональная роль NOS1AP в стабилизации функций nNOS скелетных мышц в цитоскелетном комплексе, связанном с дистрофином/утрофином. Цель обзора – предоставить обновленную информацию о роли NOS1AP и комплекса nNOS/NOS1AP в патогенезе МС и СД2. Обсуждаются потенциальные молекулярные механизмы взаимодействия NOS1AP с nNOS и другими белками, что приводит к изменению активности nNOS, ее локализации и уровня NO.

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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The authors declare that there are no conflicts of interest present.