Роль адаптерного белка нейрональной NO-синтазы в патогенезе метаболического синдрома и сахарного диабета 2 типа

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.

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