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Review
. 2024 Apr 25:15:1378315.
doi: 10.3389/fphar.2024.1378315. eCollection 2024.

Functional effects of drugs and toxins interacting with NaV1.4

Xinyi Zou #  1 , Zixuan Zhang #  1 , Hui Lu  1 , Wei Zhao  1 , Lanying Pan  2 , Yuan Chen  1
Affiliations
Review

Functional effects of drugs and toxins interacting with NaV1.4

Xinyi Zou et al. Front Pharmacol. .

Abstract

NaV1.4 is a voltage-gated sodium channel subtype that is predominantly expressed in skeletal muscle cells. It is essential for producing action potentials and stimulating muscle contraction, and mutations in NaV1.4 can cause various muscle disorders. The discovery of the cryo-EM structure of NaV1.4 in complex with β1 has opened new possibilities for designing drugs and toxins that target NaV1.4. In this review, we summarize the current understanding of channelopathies, the binding sites and functions of chemicals including medicine and toxins that interact with NaV1.4. These substances could be considered novel candidate compounds or tools to develop more potent and selective drugs targeting NaV1.4. Therefore, studying NaV1.4 pharmacology is both theoretically and practically meaningful.

Keywords: Nav1.4; drug design; mexiletine; skeletal muscle; tetrodotoxin; voltage-gated channel.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic representation of the plane of the NaV1.4 structure. CaM, calmodulin; EFL, EF-hand-like motif; IFM, IlePheMet motif.
FIGURE 2
FIGURE 2
Frequency-dependent flecainide blockage of wild-type (WT) and mutant hNaV1.4 channels at a holding potential of −120 mV. (A) Three minutes after treatment with flecainide, the Na current blockage of WT and mutants was evaluated under different stimulation frequencies. (B,C) Concentration-response fitting curve of flecainide on WT and mutants blockage at stimulation frequencies of (B) 0.1 Hz and (C) 10 Hz. (Copyright permission was obtained for the use of these images.) CTRL, Control; GE, G1306E; RC, R1448C (Desaphy et al., 2004). (Order Number:5734610752304).
FIGURE 3
FIGURE 3
Effects of cannabidiol (CBD) on NaV1.4 gating. (A,B) Voltage dependence of activation shown as normalized conductance plotted against membrane potential in 1 µM CBD, and normalized activating currents as a function of potential. (C) Voltage dependence of 200 ms F-I curve plotted against the membrane potential in 1 µM CBD. (D) Recovery from fast inactivation in 1 µM CBD at 500 ms. (E) The slow components of recovery from inactivation in the control and CBD (1 µM) at 500 ms are shown on the left y-axis (logarithmic scale), and the fraction of the slow-to-fast component of recovery from inactivation is shown on the right y-axis. (F) Use-dependent inactivation in control and 2 µM CBD. The normalized current decay is plotted as a function of time fitted with an exponential curve. (G) State-dependent block of the peak NaV1.4 current at 10 µM. (H) Pulse protocol used for state dependence experiments. Recordings were performed at 1 Hz. (Copyright permission was obtained for the use of these images.) (Ghovanloo et al., 2021) (Order Number: 1453352).
See this image and copyright information in PMC

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References

    1. Ahern C. A., Payandeh J., Bosmans F., Chanda B. (2016). The hitchhiker's guide to the voltage-gated sodium channel galaxy. J. Gen. Physiol. 147 (1), 1–24. 10.1085/jgp.201511492 - DOI - PMC - PubMed
    1. Akaba Y., Takahashi S., Sasaki Y., Kajino H. (2018). Successful treatment of normokalemic periodic paralysis with hydrochlorothiazide. Brain Dev. 40 (9), 833–836. 10.1016/j.braindev.2018.05.011 - DOI - PubMed
    1. Alfonsi E., Merlo I. M., Tonini M., Ravaglia S., Brugnoni R., Gozzini A., et al. (2007). Efficacy of propafenone in paramyotonia congenita. Neurology 68 (13), 1080–1081. 10.1212/01.wnl.0000257825.29703.e8 - DOI - PubMed
    1. Andersen G., Hedermann G., Witting N., Duno M., Andersen H., Vissing J. (2017). The antimyotonic effect of lamotrigine in non-dystrophic myotonias: a double-blind randomized study. Brain 140 (9), 2295–2305. 10.1093/brain/awx192 - DOI - PubMed
    1. Angsutararux P., Zhu W., Voelker T. L., Silva J. R. (2021). Molecular pathology of sodium channel beta-subunit variants. Front. Pharmacol. 12, 761275. 10.3389/fphar.2021.761275 - DOI - PMC - PubMed

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This research was supported by Zhejiang Provincial Natural Science Foundation of China under Grant No. LY20C040001 to LP and Grant No. LBY22H270002 to WZ; it was also supported by Scientific Research and Development Fund of Zhejiang Shuren University (2023R009) to LP.

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