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Small G—protein RhoA is a potential inhibitor of cardiac fast sodium current

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Abstract

Small G-proteins of Rho family modulate the activity of several classes of ion channels, including K+ channels Kv1.2, Kir2.1, and ERG; Ca2+ channels; and epithelial Na+ channels. The present study was aimed to check the RhoA potential regulatory effects on Na+ current (INa) transferred by Na+ channel cardiac isoform NaV1.5 in heterologous expression system and in native rat cardiomyocytes. Whole-cell patch-clamp experiments showed that coexpression of NaV1.5 with the wild-type RhoA in CHO-K1 cell line caused 2.7-fold decrease of INa density with minimal influence on steady-state activation and inactivation. This effect was reproduced by the coexpression with a constitutively active RhoA, but not with a dominant negative RhoA. In isolated ventricular rat cardiomyocytes, a 5-h incubation with the RhoA activator narciclasine (5 × 10−6 M) reduced the maximal INa density by 38.8%. The RhoA-selective inhibitor rhosin (10−5 M) increased the maximal INa density by 25.3%. Experiments with sharp microelectrode recordings in isolated right ventricular wall preparations showed that 5 × 10−6 M narciclasine induced a significant reduction of action potential upstroke velocity after 2 h of incubation. Thus, RhoA might be considered as a potential negative regulator of sodium channels cardiac isoform NaV1.5.

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Funding

The study was supported by the Russian Foundation for Basic Research [18-315-20049 to D.V.A.].

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Authors and Affiliations

  1. Department of Human and Animal Physiology, Biological faculty of the Lomonosov Moscow State University, Leninskiye Gory, 1, 12, Moscow, Russia

    Denis V. Abramochkin, Tatiana S. Filatova, Ksenia B. Pustovit & Irina Dzhumaniiazova

  2. Ural Federal University, Mira, 19, Ekaterinburg, Russia

    Denis V. Abramochkin

  3. Department of Physiology, Pirogov Russian National Research Medical University, Ostrovityanova str., 1, Moscow, Russia

    Denis V. Abramochkin, Tatiana S. Filatova & Ksenia B. Pustovit

  4. Laboratory of Cardiac Physiology, Institute of Physiology of Коmi Science Centre of the Ural Branch of the Russian Academy of Sciences, FRC Komi SC UB RAS, 167982, Pervomayskaya str., 50, Syktyvkar, Komi Republic, Russia

    Denis V. Abramochkin

  5. Almazov National Medical Research Centre, Saint-Petersburg, Russia

    Alexey V. Karpushev

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  1. Denis V. Abramochkin
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Correspondence to Denis V. Abramochkin.

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The investigation complies with the ARRIVE guidelines and conforms to the guidelines from Directive 2010/63/EU of the European Parliament on the protection of animals used for scientific purposes and was approved by the Bioethical Committee of Moscow State University.

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Key points

• Coexpression with the RhoA inhibits Na+ current (INa) in heterologous expression system

• The RhoA activator decreases INa, while its inhibitor increases INa in rat cardiomyocytes

• In rat ventricular myocardium, the RhoA activator slows down action potential upstroke

• Thus, the RhoA might be considered as a new potential regulator of cardiac Na+ channels

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Abramochkin, D.V., Filatova, T.S., Pustovit, K.B. et al. Small G—protein RhoA is a potential inhibitor of cardiac fast sodium current. J Physiol Biochem 77, 13–23 (2021). https://doi.org/10.1007/s13105-020-00774-w

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  • DOI: https://doi.org/10.1007/s13105-020-00774-w

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