Resurgent Na+ current: A new avenue to neuronal excitability control

Cruz, Jáder Santos; Silva, Darízy F.; Ribeiro, Luciano Augusto de Araújo; Araújo, Islania Giselia Albuquerque; Magalhães, Nayara; Medeiros, Alessandra; Freitas, Christiane; Araujo, Izabella C.; Oliveira, Fernando A.

doi:10.1016/j.lfs.2011.05.016

Cited by 18 publications

(19 citation statements)

References 53 publications

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“…Consistent with known properties of persistent currents, we observed that DRG inflammation depolarized the resting membrane potential of Aβ neurons, an effect which was partially reversed by Na V β4 knockdown. Although other sodium channel α subunit isoforms can generate resurgent currents when the cytoplasmic terminal peptide of Na V β4 is introduced intracellularly, in vivo, fast TTX-sensitive resurgent currents in most though not all of the neurons studied to date seem likely to be the result of Na V β4 in association with Na V 1.6, in both central and DRG neurons [10; 12; 13; 29]. The upregulation of Na V β4 in the DRG inflammation model is a plausible mechanism for facilitating the high frequency repetitive firing seen in spontaneously active Aβ neurons.…”

Section: Discussionmentioning

confidence: 99%

“…Na V 1.6 can also give rise to a resurgent sodium current, a brief reopening observed during repolarization or following an action potential [13; 33]. Na V 1.6 does not give rise to resurgent currents when expressed in heterologous expression systems, and not all neurons expressing Na V 1.6 have resurgent currents [12]. In vivo, each pore-forming α subunit associates with one or more regulatory β subunits [22].…”

Section: Introductionmentioning

confidence: 99%

“…This protein has high expression levels in the DRG neurons [53]. Resurgent current allows high frequency repetitive and bursting firing [12; 25; 32], like that observed in DRG neurons after DRG inflammation, spinal nerve ligation, and other pain models.…”

Section: Introductionmentioning

confidence: 99%

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Upregulation of the sodium channel NaVβ4 subunit and its contributions to mechanical hypersensitivity and neuronal hyperexcitability in a rat model of radicular pain induced by local dorsal root ganglion inflammation

Xie

Tan

Barbosa

et al. 2016

Pain

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High frequency spontaneous firing in myelinated sensory neurons plays a key role in initiating pain behaviors in several different models, including the radicular pain model in which the rat lumbar dorsal root ganglia (DRG) are locally inflamed. The sodium channel isoform NaV1.6 contributes to pain behaviors and spontaneous activity in this model. Among all the isoforms in adult DRG, NaV1.6 is the main carrier of TTX-sensitive resurgent Na currents that allow high-frequency firing. Resurgent currents flow after a depolarization or action potential, as a blocking particle exits the pore. In most neurons the regulatory β4 subunit is potentially the endogenous blocker. We used in vivo siRNA mediated knockdown of NaVβ4 to examine its role in the DRG inflammation model. NaVβ4 but not control siRNA almost completely blocked mechanical hypersensitivity induced by DRG inflammation. Microelectrode recordings in isolated whole DRGs showed that NaVβ4 siRNA blocked the inflammation-induced increase in spontaneous activity of Aβ neurons, and reduced repetitive firing and other measures of excitability. NaVβ4 was preferentially expressed in larger diameter cells; DRG inflammation increased its expression and this was reversed by NaVβ4 siRNA, based on immunohistochemistry and Western blotting. NaVβ4 siRNA also reduced immunohistochemical NaV1.6 expression. Patch clamp recordings of TTX-sensitive Na currents in acutely cultured medium diameter DRG neurons showed that DRG inflammation increased transient and especially resurgent current; effects blocked by NaVβ4 siRNA. NaVβ4 may represent a more specific target for pain conditions that depend on myelinated neurons expressing NaV1.6.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Upregulation of the sodium channel NaVβ4 subunit and its contributions to mechanical hypersensitivity and neuronal hyperexcitability in a rat model of radicular pain induced by local dorsal root ganglion inflammation

Xie

Tan

Barbosa

et al. 2016

Pain

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“…Sensory neurons express the Na V 1.6 sodium channel isoform (Black et al, 2002, Dib-Hajj et al, 2010), which can give rise to resurgent currents that facilitate high frequency firing (Cruz et al, 2011). We previously showed that small inhibitory (si) RNA-mediated knockdown of the Na V 1.6 channel in vivo could prevent pain behaviors and spontaneous activity induced by localized inflammation of the lumbar DRG (Xie et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Local knockdown of the NaV1.6 sodium channel reduces pain behaviors, sensory neuron excitability, and sympathetic sprouting in rat models of neuropathic pain

2015

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In the spinal nerve ligation model of neuropathic pain, as in other pain models, abnormal spontaneous activity of myelinated sensory neurons occurs early and is essential for establishing pain behaviors and other pathologies. Sympathetic sprouting into the dorsal root ganglion (DRG) is observed after spinal nerve ligation, and sympathectomy reduces pain behavior. Sprouting and spontaneous activity may be mutually reinforcing: blocking neuronal activity reduces sympathetic sprouting, and sympathetic spouts functionally increase spontaneous activity in vitro. However, most studies in this field have used nonspecific methods to block spontaneous activity, methods that also block evoked and normal activity. In this study, we injected small inhibitory RNA directed against the NaV1.6 sodium channel isoform into the DRG before spinal nerve ligation. This isoform can mediate high frequency repetitive firing, like that seen in spontaneously active neurons. Local knockdown of NaV1.6 markedly reduced mechanical pain behaviors induced by spinal nerve ligation, reduced sympathetic sprouting into the ligated sensory ganglion, and blocked abnormal spontaneous activity and other measures of hyperexcitability in myelinated neurons in the ligated sensory ganglion. Immunohistochemical experiments showed that sympathetic sprouting preferentially targeted NaV1.6-positive neurons. Under these experimental conditions, NaV1.6 knockdown did not prevent or strongly alter single evoked action potentials, unlike previous less specific methods used to block spontaneous activity. NaV1.6 knockdown also reduced pain behaviors in another pain model, chronic constriction of the sciatic nerve, provided the model was modified so that the lesion site was relatively close to the siRNA-injected lumbar DRGs. The results highlight the relative importance of abnormal spontaneous activity in establishing both pain behaviors and sympathetic sprouting, and suggest that the NaV1.6 isoform may have value as a therapeutic target.

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“…Na v 1.6 has a lower threshold for generation of action potentials than Na v 1.1 and Na v 1.2, the other major brain channels (Spampanato et al, 2001; Rush et al, 2005; Chen et al, 2008), and is an important source of persistent and resurgent sodium current (Raman et al, 1997; Royeck et al, 2008; O'Brien and Meisler, 2013). These properties of Na v 1.6 contribute to the generation of bursts of action potentials in repetitively firing neurons such as Purkinje cells (Raman et al, 1997; Lorincz and Nusser, 2008; Cruz et al, 2011). Nav1.6 is the major sodium channel at the AIS of cerebellar Purkinje cells, repetitively firing neurons that exhibit bursts of action potentials (Lorincz and Nusser, 2008).…”

Section: Introductionmentioning

confidence: 99%

Single amino acid deletion in transmembrane segment D4S6 of sodium channel Scn8a (Nav1.6) in a mouse mutant with a chronic movement disorder

Jones

Dionne

Dell’Orco

et al. 2016

Neurobiology of Disease

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Mutations of the neuronal sodium channel gene SCN8A are associated with lethal movement disorders in the mouse and with human epileptic encephalopathy. We describe a spontaneous mouse mutation, Scn8a 9J, that is associated with a chronic movement disorder with early onset tremor and adult onset dystonia. Scn8a 9J homozygotes have a shortened lifespan, with only 50% of mutants surviving beyond 6 months of age. The 3 bp in-frame deletion removes 1 of the 3 adjacent isoleucine residues in transmembrane segment DIVS6 of Nav1.6 (p.Ile1750del). The altered helical orientation of the transmembrane segment displaces pore-lining amino acids with important roles in channel activation and inactivation. The predicted impact on channel activity was confirmed by analysis of cerebellar Purkinje neurons from mutant mice, which lack spontaneous and induced repetitive firing. In a heterologous expression system, the activity of the mutant channel was below the threshold for detection. Observations of decreased nerve conduction velocity and impaired behavior in an open field are also consistent with reduced activity of Nav1.6. The Nav1.6Δ1750 protein is only partially glycosylated. The abundance of mutant Nav1.6 is reduced at nodes of Ranvier and is not detectable at the axon initial segment. Despite a severe reduction in channel activity, the lifespan and motor function of Scn8a9J/9J mice are significantly better than null mutants lacking channel protein. The clinical phenotype of this severe hypomorphic mutant expands the spectrum of Scn8a disease to include a recessively inherited, chronic and progressive movement disorder.

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Resurgent Na+ current: A new avenue to neuronal excitability control

Cited by 18 publications

References 53 publications

Upregulation of the sodium channel NaVβ4 subunit and its contributions to mechanical hypersensitivity and neuronal hyperexcitability in a rat model of radicular pain induced by local dorsal root ganglion inflammation

Upregulation of the sodium channel NaVβ4 subunit and its contributions to mechanical hypersensitivity and neuronal hyperexcitability in a rat model of radicular pain induced by local dorsal root ganglion inflammation

Local knockdown of the NaV1.6 sodium channel reduces pain behaviors, sensory neuron excitability, and sympathetic sprouting in rat models of neuropathic pain

Single amino acid deletion in transmembrane segment D4S6 of sodium channel Scn8a (Nav1.6) in a mouse mutant with a chronic movement disorder

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