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Transient Receptor Potential Vanilloid 4-Induced Modulation of Voltage-Gated Sodium Channels in Hippocampal Neurons

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Abstract

Transient receptor potential vanilloid 4 (TRPV4) is reported to control the resting membrane potential and increase excitability in many types of cells. Voltage-gated sodium channels (VGSCs) play an important role in initiating action potentials in neurons. However, whether VGSCs can be modulated by the activation of TRPV4 in hippocampal pyramidal neurons remains unknown. In this study, we tested the effect of TRPV4 agonists (GSK1016790A and 4α-PDD) on voltage-gated sodium current (I Na) in hippocampal CA1 pyramidal neurons and the protein levels of α/β-subunit of VGSCs in the hippocampus of mice subjected to intracerebroventricular (icv.) injection of GSK1016790A (GSK-injected mice). Herein, we report that I Na was inhibited by acute application of GSK1016790A or 4α-PDD. In the presence of TRPV4 agonists, the voltage-dependent inactivation curve shifted to the hyperpolarization, whereas the voltage-dependent activation curve remained unchanged. The TRPV4 agonist-induced inhibition of I Na was blocked by the TRPV4 antagonist or tetrodotoxin. Moreover, blocking protein kinase A (PKA) markedly attenuated the GSK1016790A-induced inhibition of I Na, whereas antagonism of protein kinase C or p38 mitogen-activated protein kinase did not change GSK1016790A action. Finally, the protein levels of Nav1.1, Nav1.2, and Nav1.6 in the hippocampus increased in GSK-injected mice, whereas those of Nav1.3 and Navβ1 remained nearly unchanged. We conclude that I Na is inhibited by the acute activation of TRPV4 through PKA signaling pathway in hippocampal pyramidal neurons, but protein expression of α-subunit of VGSCs is increased by sustained TRPV4 activation, which may compensate for the acute inhibition of I Na and provide a possibility for hyper-excitability upon sustained TRPV4 activation.

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Acknowledgments

This work was supported by National Natural Science Foundation of China (31271206), Research Award Fund for Outstanding Young Teachers in Nanjing Medical University (JX2161015033) and Qing Lan Project of Jiangsu province (2014–2017).

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.

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Authors and Affiliations

  1. Department of Physiology, Nanjing Medical University, No. 140, Hanzhong Road, Nanjing, 210029, China

    Zhiwen Hong, Pinghui Jie, Yujing Tian, Tingting Chen, Lei Chen & Ling Chen

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  1. Zhiwen Hong
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  2. Pinghui Jie
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  3. Yujing Tian
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Correspondence to Lei Chen.

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Supplementary Fig. 1

I Na and GSK1016790A-evoked current recorded in hippocampal CA1 pyramidal neurons. When recording TRPV4-mediated current, 500 nM GSK1016790A and 0.3 μM TTX were added to mASCF and a ramp protocol depolarizing from −80 to +80 mV over 700 ms was used. Typical recordings show that I Na (a) and GSK1016790A-induced current (b) were recorded in the same neuron. (GIF 5 kb)

High resolution image (TIFF 1240 kb)

Supplementary Fig. 2

Effect of BAPTA-AM on GSK1016790A-induced inhibition of I Na in hippocampal CA1 pyramidal neurons. GAK1016790A-induced inhibition of I Na was partially blocked by pre-application of BAPTA-AM (10 μM). The dose of BATPA-AM was used as previously reported [1] *p<0.05 vs. GSK1016790A 1. Aflaki M, Qi XY, Xiao L, Ordog B, Tadevosyan A, Luo X, Maguy A, Shi Y, Tardif JC, Nattel S (2014) Exchange protein directly activated by cAMP mediates slow delayed-rectifier current remodeling by sustained β-adrenergic activation in guinea pig hearts. Circ Res 114(6):993–1003. (GIF 18 kb)

High resolution image (TIFF 20629 kb)

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Hong, Z., Jie, P., Tian, Y. et al. Transient Receptor Potential Vanilloid 4-Induced Modulation of Voltage-Gated Sodium Channels in Hippocampal Neurons. Mol Neurobiol 53, 759–768 (2016). https://doi.org/10.1007/s12035-014-9038-5

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