Downregulation of adult and neonatal Nav1.5 in the dorsal root ganglia and axon of peripheral sensory neurons of rats with spared nerve injury

Wang,Jun; Ou,Shao-Wu; Bai,Yun-Fei; Wang,Yun-Jie; Xu,Zhi-Qing  David; Luan,Guo-Ming

doi:10.3892/ijmm.2018.3446

Downregulation of adult and neonatal Nav1.5 in the dorsal root ganglia and axon of peripheral sensory neurons of rats with spared nerve injury

Authors:
- Jun Wang
- Shao-Wu Ou
- Yun-Fei Bai
- Yun-Jie Wang
- Zhi-Qing David Xu
- Guo-Ming Luan
View Affiliations

Affiliations: Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing 100093, P.R. China, Department of Neurosurgery, The First Hospital of China Medical University, Shenyang 110001, P.R. China, Beijing Key Laboratory of Neural Regeneration and Repair, Department of Neurobiology, Capital Medical University, Beijing 100069, P.R. China
Published online on: January 30, 2018 https://doi.org/10.3892/ijmm.2018.3446
Pages: 2225-2232

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Previous studies demonstrated that Nav1.5 splice variants, including Nav1.5a and Nav1.5c, were expressed in dorsal root ganglia (DRG) neurons. However, since nine Nav1.5 isoforms have been identified, whether other Nav1.5 splice variants, especially the neonatal Nav1.5 splice variant, express in the DRG neurons is still unknown. In this study, we systematically investigated the expression of adult and neonatal Nav1.5 isoforms in the DRG neurons and axon of peripheral sensory neurons of rats with spared nerve injury (SNI) by RT-PCR, DNA sequencing, restriction enzyme digestion, immunohistochemistry and immunofluorescence methods. The results demonstrated that both adult and neonatal Nav1.5 isoforms were expressed in the DRG neurons, but their expression ratio was ~2.5:1. In SNI rat models, the expression of both adult and neonatal Nav1.5 decreased by approximately a half in both mRNA and protein levels. In contrast, the expression of protein kinase C (PKC)-γ, one of the negative modulators for sodium currents, increased by ~1-fold. Taken together, this study first confirmed the expression of both adult and neonatal Nav1.5 isoforms in the DRG neurons and axon of peripheral sensory neurons of rat, but their expression level decreased in pain models. The upregulation of PKC-γ may directly or indirectly downregulate the expression of Nav1.5 isoforms in SNI rat models, which may further involve in the pathological process of neuropathic pain.

View Figures

View References

1	Liu M and Wood JN: The roles of sodium channels in nociception: Implications for mechanisms of neuropathic pain. Pain Med. 12(Suppl 3): S93–S99. 2011. View Article : Google Scholar : PubMed/NCBI
2	Cummins TR, Sheets PL and Waxman SG: The roles of sodium channels in nociception: Implications for mechanisms of pain. Pain. 131:243–1257. 2007. View Article : Google Scholar : PubMed/NCBI
3	Catterall WA: From ionic currents to molecular mechanisms: The structure and function of voltage-gated sodium channels. Neuron. 26:13–125. 2000. View Article : Google Scholar : PubMed/NCBI
4	Yu FH and Catterall WA: Overview of the voltage-gated sodium channel family. Genome Biol. 4:2072003. View Article : Google Scholar : PubMed/NCBI
5	Catterall WA: Voltage-gated sodium channels at 60: Structure, function and pathophysiology. J Physiol. 590:2577–12589. 2012. View Article : Google Scholar : PubMed/NCBI
6	Laedermann CJ, Pertin M, Suter MR and Decosterd I: Voltage-gated sodium channel expression in mouse DRG after SNI leads to re-evaluation of projections of injured fibers. Mol Pain. 10:192014. View Article : Google Scholar : PubMed/NCBI
7	Devor M: Sodium channels and mechanisms of neuropathic pain. J Pain. 7(Suppl 1): S3–S12. 2006. View Article : Google Scholar : PubMed/NCBI
8	Rook MB, Evers MM, Vos MA and Bierhuizen MF: Biology of cardiac sodium channel Nav1.5 expression. Cardiovasc Res. 93:12–123. 2012. View Article : Google Scholar
9	Schroeter A, Walzik S, Blechschmidt S, Haufe V, Benndorf K and Zimmer T: Structure and function of splice variants of the cardiac voltage-gated sodium channel Na(v)1.5. J Mol Cell Cardiol. 49:16–124. 2010. View Article : Google Scholar : PubMed/NCBI
10	Wang J, Ou SW, Wang YJ, Kameyama M, Kameyama A and Zong ZH: Analysis of four novel variants of Nav1.5/SCN5A cloned from the brain. Neurosci Res. 64:339–1347. 2009. View Article : Google Scholar : PubMed/NCBI
11	Wang J, Ou SW, Wang YJ, Zong ZH, Lin L, Kameyama M and Kameyama A: New variants of Nav1.5/SCN5A encode Na⁺ channels in the brain. J Neurogenet. 22:57–175. 2008. View Article : Google Scholar : PubMed/NCBI
12	Xing D, Wang J, Ou S, Wang Y, Qiu B, Ding D, Guo F and Gao Q: Expression of neonatal Nav1.5 in human brain astrocytoma and its effect on proliferation, invasion and apoptosis of astrocytoma cells. Oncol Rep. 31:2692–12700. 2014. View Article : Google Scholar : PubMed/NCBI
13	Renganathan M, Dib-Hajj S and Waxman SG: Na(v)1.5 underlies the 'third TTX-R sodium current' in rat small DRG neurons. Brain Res Mol Brain Res. 106:70–182. 2002. View Article : Google Scholar : PubMed/NCBI
14	Kerr NC, Holmes FE and Wynick D: Novel isoforms of the sodium channels Nav1.8 and Nav1.5 are produced by a conserved mechanism in mouse and rat. J Biol Chem. 279:24826–124833. 2004. View Article : Google Scholar : PubMed/NCBI
15	Kerr NC, Gao Z, Holmes FE, Hobson SA, Hancox JC, Wynick D and James AF: The sodium channel Nav1.5a is the predominant isoform expressed in adult mouse dorsal root ganglia and exhibits distinct inactivation properties from the full-length Nav1.5 channel. Mol Cell Neurosci. 35:283–1291. 2007. View Article : Google Scholar : PubMed/NCBI
16	Ren CT, Li DM, Ou SW, Wang YJ, Lin Y, Zong ZH, Kameyama M and Kameyama A: Cloning and expression of the two new variants of Nav1.5/SCN5A in rat brain. Mol Cell Biochem. 365:139–1148. 2012. View Article : Google Scholar : PubMed/NCBI
17	Hartmann HA, Colom LV, Sutherland ML and Noebels JL: Selective localization of cardiac SCN5A sodium channels in limbic regions of rat brain. Nat Neurosci. 2:593–1595. 1999. View Article : Google Scholar : PubMed/NCBI
18	Wu L, Nishiyama K, Hollyfield JG and Wang Q: Localization of Nav1.5 sodium channel protein in the mouse brain. Neuroreport. 13:2547–12551. 2002. View Article : Google Scholar : PubMed/NCBI
19	Frenz CT, Hansen A, Dupuis ND, Shultz N, Levinson SR, Finger TE and Dionne VE: NaV1.5 sodium channel window currents contribute to spontaneous firing in olfactory sensory neurons. J Neurophysiol. 112:1091–11104. 2014. View Article : Google Scholar : PubMed/NCBI
20	Onkal R, Mattis JH, Fraser SP, Diss JK, Shao D, Okuse K and Djamgoz MB: Alternative splicing of Nav1.5: An electrophysiological comparison of 'neonatal' and 'adult' isoforms and critical involvement of a lysine residue. J Cell Physiol. 216:716–1726. 2008. View Article : Google Scholar : PubMed/NCBI
21	Decosterd I and Woolf CJ: Spared nerve injury: An animal model of persistent peripheral neuropathic pain. Pain. 87:149–1158. 2000. View Article : Google Scholar : PubMed/NCBI
22	Ou SW, Kameyama A, Hao LY, Horiuchi M, Minobe E, Wang WY, Makita N and Kameyama M: Tetrodotoxin-resistant Na⁺ channels in human neuroblastoma cells are encoded by new variants of Nav1.5/SCN5A. Eur J Neurosci. 22:793–1801. 2005. View Article : Google Scholar : PubMed/NCBI
23	Fraser SP, Diss JK, Chioni AM, Mycielska ME, Pan H, Yamaci RF, Pani F, Siwy Z, Krasowska M, Grzywna Z, et al: Voltage-gated sodium channel expression and potentiation of human breast cancer metastasis. Clin Cancer Res. 11:5381–15389. 2005. View Article : Google Scholar : PubMed/NCBI
24	Wang W, Gu J, Li YQ and Tao YX: Are voltage-gated sodium channels on the dorsal root ganglion involved in the development of neuropathic pain? Mol Pain. 7:162011. View Article : Google Scholar : PubMed/NCBI
25	Moldovan M, Alvarez S, Romer Rosberg M and Krarup C: Axonal voltage-gated ion channels as pharmacological targets for pain. Eur J Pharmacol. 708:105–1112. 2013. View Article : Google Scholar : PubMed/NCBI
26	Numann R, Catterall WA and Scheuer T: Functional modulation of brain sodium channels by protein kinase C phosphorylation. Science. 254:115–1118. 1991. View Article : Google Scholar : PubMed/NCBI
27	Schreibmayer W: Isoform diversity and modulation of sodium channels by protein kinases. Cell Physiol Biochem. 9:187–1200. 1999. View Article : Google Scholar : PubMed/NCBI
28	Grant AO and Wendt DJ: Block and modulation of cardiac Na⁺ channels by antiarrhythmic drugs, neurotransmitters and hormones. Trends Pharmacol Sci. 13:352–1358. 1992. View Article : Google Scholar : PubMed/NCBI
29	Tateyama M, Kurokawa J, Terrenoire C, Rivolta I and Kass RS: Stimulation of protein kinase C inhibits bursting in disease-linked mutant human cardiac sodium channels. Circulation. 107:3216–13222. 2003. View Article : Google Scholar : PubMed/NCBI
30	Hallaq H, Wang DW, Kunic JD, George AL Jr, Wells KS and Murray KT: Activation of protein kinase C alters the intracellular distribution and mobility of cardiac Na⁺ channels. Am J Physiol Heart Circ Physiol. 302:H782–H789. 2012. View Article : Google Scholar