transmedТрансляционная медицинаTranslational Medicine2311-44952410-5155Almazov National Medical Research Centre, Saint Petersburg, Russia10.18705/2311-4495-2022-9-6-71-94transmed-739Research ArticleМОЛЕКУЛЯРНАЯ БИОЛОГИЯ И ГЕНЕТИКАМеханизмы регуляции экспрессии, транспорта и биофизической активности потенциал-зависимых натриевых каналов сердцаMechanisms of expression, trafficking and biophysical activity regulation of voltage-gated cardiac sodium channelsЗайцеваА. К.ZaytsevaA. K.

Зайцева Анастасия Константиновна, аспирант; младший научный сотрудник, НИЛ молекулярного и клеточного моделирования и генной терапии, НИЦ неизвестных, редких и генетически обусловленных заболеваний

ул. Аккуратова, д. 2, Санкт-Петербург, 19734

Anastasia K. Zaytseva, postgraduate student; junior researcher, Research Laboratory of Molecular and Cellular Modeling and Gene Therapy, Research Centre of Unknown, Rare and Genetically Determined Diseases

Akkuratova str., 2, Saint Petersburg, 197341

zaytseva.anastasia.zak@gmail.comКостареваА. А.KostarevaA. A.

Костарева Анна Александровна, д.м.н., директор Института молекулярной биологии и генетики, заведующий НИЛ молекулярного и клеточного моделирования и генной терапии, НИЦ неизвестных, редких и генетически обусловленных заболеваний

Санкт-Петербург

Anna A. Kostareva, D.M.Sc., Ph.D., Head of Research Laboratory of Molecular and Cellular Modeling and Gene Therapy, Research Centre of Unknown, Rare and Genetically Determined Diseases; head of Institute of Molecular Biology and Genetics

Saint Petersburg

Федеральное государственное бюджетное учреждение «Национальный медицинский исследовательский центр имени В. А. Алмазова» Министерства здравоохранения Российской Федерации, Научный центр мирового уровня «Центр персонализированной медицины»; Федеральное государственное бюджетное учреждение науки «Институт эволюционной физиологии и биохимии имени И. М. Сеченова Российской академии наук»РоссияAlmazov National Medical Research Centre, World-Class Research Centre for Personalized Medicine; Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of SciencesRussian FederationФедеральное государственное бюджетное учреждение «Национальный медицинский исследовательский центр имени В. А. Алмазова» Министерства здравоохранения Российской Федерации, Научный центр мирового уровня «Центр персонализированной медицины»Russian FederationAlmazov National Medical Research Centre, World-Class Research Centre for Personalized MedicineRussian Federation202202032023967194Copyright © Зайцева А.К., Костарева А.А., 20232023Зайцева А.К., Костарева А.А.Zaytseva A.K., Kostareva A.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://transmed.almazovcentre.ru/jour/article/view/739

Генетические варианты в гене SCN5A, кодирующем сердечную изоформу потенциал-зависимого натриевого канала NaV1.5,были обнаружены у множества пациентов с различными наследственными заболеваниями сердца. Актуальными проблемами современной электрофизиологии являются, с одной стороны, поиск механизмов развития заболевания и, с другой — поиск способов коррекции дисфункции натриевого тока при патологических состояниях.

В последние десятилетия был достигнут значительный прогресс в понимании жизненного цикла NaV1.5 и особенностей распределения каналов в различных микродоменах плазматической мембраны.

Регуляция NaV1.5 осуществляется на всех возможных уровнях от экспрессии SCN5A до контроля убиквитин-зависимой деградации. В зависимости от микродомена плазматической мембраны NaV1.5 входит в состав различных макромолекулярных комплексов. Так, в латеральной мембране NaV1.5 ко-локализован с дистрофин-синтрофиновым комплексом, а в области вставочного диска натриевые каналы находятся в окружении десмосомальных белков, G-анкирина, белков щелевых контактов. В данном обзоре систематизированы знания о белковых-партнерах NaV1.5 в разных участках мембраны кардиомиоцитов, а также о посттрансляционных модификациях NaV1.5. Отдельное внимание уделяется вопросам потенциального клинического применения. Рассмотрены варианты терапии, направленные на синтез SCN5A, транспорт NaV1.5 и поздний натриевый ток. Таким образом, изучение механизмов регуляции функционирования α-NaV1.5 в будущем сыграет важную роль не только в понимании биологии и патофизиологии NaV1.5, но и в поиске новых перспективных методов терапии.

Genetic variants in the SCN5A gene, encoding the cardiac isoform of the NaV1.5 voltage-gated sodium channel, were observed in patients with various hereditary heart diseases. Actual problems of modern electrophysiology covers the search for mechanisms of the disease development and the search for approaches to correct sodium current dysfunction in pathological conditions.

In recent decades, significant progress has been achieved in understanding the life cycle of NaV1.5 and the distribution of channels in various microdomains of the plasma membrane.

NaV1.5 is regulated at all possible levels from SCN5A expression to control of ubiquitin-dependent degradation. Depending on the microdomain of the plasma membrane, NaV1.5 is part of various macromolecular complexes. Thus, in the lateral membrane, NaV1.5 is co-localized with the dystrophin-syntrophin complex, and in the region of the intercalated disc, sodium channels are surrounded by desmosomal proteins, G-ankyrin, and gap junction proteins. This review systematizes knowledge about NaV1.5 protein partners in different regions of the cardiomyocyte membrane, as well as about post-translational modifications of NaV1.5. Special attention is paid to potential clinical applications. Therapy strategies targeting SCN5A synthesis, NaV1.5 transport, and late sodium current are considered. Thus, the study of the mechanisms regulating the functioning of α-NaV1.5 in the future will play an important role not only in understanding the biology and pathophysiology of NaV1.5, but also in the search for new promising methods of therapy.

аритмиидифференциальное распределение ионных каналов в мембранепосттрансляционные модификациипотенциал-зависимые натриевые каналы сердцарегуляцияNaV1.5.arrhythmiacardiac voltage-gated sodium channelsdifferential distribution of ion channels in the membraneNaV1.5post-translational modificationsregulationРабота поддержана грантом РФФИ №20-34-90142 «Связь наследственных нарушений сердечного ритма с процессами инактивации потенциал-зависимого натриевого канала Nav1.5».The work was supported by RFBR grant No. 20-34-90142 «The relationship of hereditary heart rhythm disorders with the processes of inactivation of the potentialdependent sodium channel Nav1.5».ReferencesD. Jiang, H. Shi, L. Tonggu, T.M. Gamal El-Din, M.J. Lenaeus, Y. Zhao, C. Yoshioka, N. Zheng, W.A. Catterall, Structure of the Cardiac Sodium Channel, Cell 180 (2020) 122-134.e110. 10.1016/j.cell.2019.11.041.D. Jiang, H. Shi, L. Tonggu, T.M. Gamal El-Din, M.J. Lenaeus, Y. Zhao, C. Yoshioka, N. Zheng, W.A. 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The authors declare that there are no conflicts of interest present.