Analysis of four novel variants of Nav1.5/SCN5A cloned from the brain

Wang, Jun; Ou, Shaowu; Kameyama, Masaki; Kameyama, Asako; Zong, Zhi‐Hong

doi:10.1016/j.neures.2009.04.003

Cited by 23 publications

(35 citation statements)

References 34 publications

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“…The 5' neonatal isoform can be expressed at birth, while the 3' mature isoform is expressed later in development (37). Our study confirmed that the nNav1.5 Na + channel is widely expressed in rat CNS (9,28). However, it is worth noting that the average expression level of nNav1.5 showed a downward trend as the age of the rats increased (7,9,27,30), indicating that it is mainly expressed in immature neurons or glial cells, further suggesting that the expression of nNav1.5 may be the result of the re-expression of an embryonic gene or oncogene.…”

Section: Discussionsupporting

confidence: 81%

“…The results showed that the SCN5A gene which encodes Nav1.5 in brain tissue is different than that in human cardiomyocytes, and they belong to two different subtypes. The former is a neonatal isoform (6,7,9,(28)(29)(30)(31), namely nNav1.5 (neonatal Nav1.5), while the latter is a mature isoform. Our and various other studies suggest that the Nav1.5 subtype of VGSCs encoded by the SCN5A gene could potentially serve as a marker of tumor metastasis and as a therapeutic target (8,(10)(11)(12)26,(30)(31)(32)(33)(34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, Na + channels are expected to become a new target for gene therapy for astrocytoma (3)(4)(5)(6). Our previous studies found that a new neonatal isoform of the Nav1.5 Na + channel, neonatal Nav1.5 (nNav1.5), was functionally expressed in human brain neuroblastoma NB-1 cells (7)(8)(9). This neonatal isoform is considered to be the re-expression of an embryonic gene or oncogene, and its expression is intimately related to the occurrence and development of tumors, which has been confirmed in lymphoma and breast cancer (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

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Expression of neonatal Nav1.5 in human brain astrocytoma and its effect on proliferation, invasion and apoptosis of astrocytoma cells

Xing

Wang

et al. 2014

Oncology Reports

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Abstract. In the present study, we designed and conducted a series of assays to determine the expression of voltage-gated sodium channel (VGSC) neonatal isoform Nav1.5 (nNav1.5) in human brain astrocytoma and its effect on the proliferation, migration, invasion and apoptosis of astrocytoma U251 cells. The results showed that nNav1.5 mRNA and protein were expressed in both human brain astrocytoma and normal brain tissues, but their expression levels in astrocytoma were significantly higher (P<0.05). In astrocytomas, nNav1.5 mRNA and protein levels were also different (P<0.05) and were correlated with pathological grades. The immunofluorescence confocal microscopy observations demonstrated that nNav1.5 protein was expressed in the nucleus, cytoplasm and membrane of the astrocytoma cells. After transfection, the small interfering RNA (siRNA) targeted to nNav1.5 significantly reduced the expression levels of SCN5A/nNav1.5 mRNA and protein by 57.2% (P<0.05) and 66.6% (P<0.05), respectively. The MTT, wound healing, Matrigel invasion and flow cytometric assays confirmed that following siRNA downregulation of the expression of the SCN5A/nNav1.5 gene, the in vitro proliferation and in vitro invasiveness of the U251 cells were significantly reduced (P<0.05 for both comparisons), and the apoptosis rate was significantly increased (P<0.05). These results revealed that nNav1.5 expression in human brain astrocytoma was upregulated, and its expression was positively correlated with the degree of malignancy. Additionally, reduced nNav1.5 expression significantly suppressed the proliferation and invasiveness of astrocytoma cells, indicating a new target in the molecular diagnosis and therapy of astrocytoma.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Expression of neonatal Nav1.5 in human brain astrocytoma and its effect on proliferation, invasion and apoptosis of astrocytoma cells

Xing

Wang

et al. 2014

Oncology Reports

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“…Our study confirms the expression of Na V 1.7 but adds that Na V 1.5, the TTX-R cardiac subtype, is also expressed in mouse OSNs. While Na V 1.5 is not widely expressed in neurons, low levels have been detected in brain (Wang et al 2009), macrophages (Carrithers et al 2007), and embryonic dorsal root ganglia (Rush et al 2007), and a truncated isoform is expressed in adult mouse dorsal root ganglia (Kerr et al 2007). …”

Section: Discussionmentioning

confidence: 99%

Na_V1.5 sodium channel window currents contribute to spontaneous firing in olfactory sensory neurons

Frenz

Hansen

Dupuis

et al. 2014

Journal of Neurophysiology

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Frenz CT, Hansen A, Dupuis ND, Shultz N, Levinson SR, Finger TE, Dionne VE. Na V 1.5 sodium channel window currents contribute to spontaneous firing in olfactory sensory neurons. J Neurophysiol 112: 1091-1104. First published May 28, 2014 doi:10.1152/jn.00154.2014.-Olfactory sensory neurons (OSNs) fire spontaneously as well as in response to odor; both forms of firing are physiologically important. We studied voltage-gated Na ϩ channels in OSNs to assess their role in spontaneous activity. Whole cell patchclamp recordings from OSNs demonstrated both tetrodotoxin-sensitive and tetrodotoxin-resistant components of Na ϩ current. RT-PCR showed mRNAs for five of the nine different Na ϩ channel ␣-subunits in olfactory tissue; only one was tetrodotoxin resistant, the so-called cardiac subtype Na V 1.5. Immunohistochemical analysis indicated that Na V 1.5 is present in the apical knob of OSN dendrites but not in the axon. The Na V 1.5 channels in OSNs exhibited two important features: 1) a half-inactivation potential near Ϫ100 mV, well below the resting potential, and 2) a window current centered near the resting potential. The negative half-inactivation potential renders most Na V 1.5 channels in OSNs inactivated at the resting potential, while the window current indicates that the minor fraction of noninactivated Na V 1.5 channels have a small probability of opening spontaneously at the resting potential. When the tetrodotoxin-sensitive Na ϩ channels were blocked by nanomolar tetrodotoxin at the resting potential, spontaneous firing was suppressed as expected. Furthermore, selectively blocking Na V 1.5 channels with Zn 2ϩ in the absence of tetrodotoxin also suppressed spontaneous firing, indicating that Na V 1.5 channels are required for spontaneous activity despite resting inactivation. We propose that window currents produced by noninactivated Na V 1.5 channels are one source of the generator potentials that trigger spontaneous firing, while the upstroke and propagation of action potentials in OSNs are borne by the tetrodotoxin-sensitive Na ϩ channel subtypes.

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“…Of interest, a recent report found splice variant differences between brain and cardiac Na v 1.5 in both rat and human, and suggested that the properties of the cardiac and brain versions of the channel may therefore differ. 59 Most interest in selective sodium channel drug discovery centers on Na v 1.3, Na v 1.7, Na v 1.8, and Na v 1.9, and the evidence that these channels contribute to neuropathic pain will be briefly reviewed. Recent clinical descriptions of Na v 1.7 gain and loss of function mutations in probands from affected families have brought a great deal of attention to the role of this channel in all forms of pain perception, as described in greater detail below.…”

Section: Sodium Channels and Painmentioning

confidence: 99%

Sodium Channel Blockers for the Treatment of Neuropathic Pain

2009

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Summary:Drugs that block voltage-gated sodium channels are efficacious in the management of neuropathic pain. Accordingly, this class of ion channels has been a major focus of analgesic research both in academia and in the pharmaceutical/biotechnology industry. In this article, we review the history of the use of sodium channel blockers, describe the current status of sodium channel drug discovery, highlight the challenges and hurdles to attain sodium channel subtype selectivity, and review the potential usefulness of selective sodium channel blockers in neuropathic pain.

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Analysis of four novel variants of Nav1.5/SCN5A cloned from the brain

Cited by 23 publications

References 34 publications

Expression of neonatal Nav1.5 in human brain astrocytoma and its effect on proliferation, invasion and apoptosis of astrocytoma cells

Expression of neonatal Nav1.5 in human brain astrocytoma and its effect on proliferation, invasion and apoptosis of astrocytoma cells

Na_V1.5 sodium channel window currents contribute to spontaneous firing in olfactory sensory neurons

Sodium Channel Blockers for the Treatment of Neuropathic Pain

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Analysis of four novel variants of Nav1.5/SCN5A cloned from the brain

Cited by 23 publications

References 34 publications

Expression of neonatal Nav1.5 in human brain astrocytoma and its effect on proliferation, invasion and apoptosis of astrocytoma cells

Expression of neonatal Nav1.5 in human brain astrocytoma and its effect on proliferation, invasion and apoptosis of astrocytoma cells

NaV1.5 sodium channel window currents contribute to spontaneous firing in olfactory sensory neurons

Sodium Channel Blockers for the Treatment of Neuropathic Pain

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Na_V1.5 sodium channel window currents contribute to spontaneous firing in olfactory sensory neurons