Voltage‐gated sodium channels: (Na<sub>V</sub>)igating the field to determine their contribution to visceral nociception

Erickson, Andelain; Deiteren, Annemie; Harrington, Andrea M.; Garcia‐Caraballo, Sonia; Castro, Joel; Caldwell, Ashlee; Grundy, Luke; Brierley, Stuart M.

doi:10.1113/jp273461

Cited by 38 publications

(33 citation statements)

References 163 publications

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“…, ; Erickson et al . ). A contribution of Na V 1.6 channels to enhanced excitability of sensory neurons is supported by evidence from human genetic studies and murine models suggesting that Na V 1.6 plays a significant role in the development and maintenance of trigeminal neuralgia and neuropathic pain (Ren et al .…”

Section: Discussionmentioning

confidence: 97%

“…These fibres responded to noxious distension (40 mmHg), circular stretch (≥7 g) or 2 g filament probing, but not to fine mucosal stroking (10 mg filament), and they express an array of channels and receptors involved in pain, become mechanically hypersensitive in models of chronic visceral pain, and have a nociceptor phenotype (Erickson et al . ; Sadeghi et al . ).…”

Section: Methodsmentioning

confidence: 99%

“…, ; Erickson et al . ). Na V 1.6 channels are expressed in both the central and peripheral nervous system where they are the major Na V isoform at the nodes of Ranvier and are also present in unmyelinated fibres and at the nerve terminals of a subset of sensory neurons (Caldwell et al .…”

Section: Introductionmentioning

confidence: 97%

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Na_V1.6 regulates excitability of mechanosensitive sensory neurons

Israel

Tanaka

Castro

et al. 2019

The Journal of Physiology

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Key points Voltage‐gated sodium channels are critical for peripheral sensory neuron transduction and have been implicated in a number of painful and painless disorders. The β‐scorpion toxin, Cn2, is selective for NaV1.6 in dorsal root ganglion neurons. NaV1.6 plays an essential role in peripheral sensory neurons, specifically at the distal terminals of mechanosensing fibres innervating the skin and colon. NaV1.6 activation also leads to enhanced response to mechanical stimulus in vivo. This works highlights the use of toxins in elucidating pain pathways moreover the importance of non‐peripherally restricted NaV isoforms in pain generation. Abstract Peripheral sensory neurons express multiple voltage‐gated sodium channels (NaV) critical for the initiation and propagation of action potentials and transmission of sensory input. Three pore‐forming sodium channel isoforms are primarily expressed in the peripheral nervous system (PNS): NaV1.7, NaV1.8 and NaV1.9. These sodium channels have been implicated in painful and painless channelopathies and there has been intense interest in them as potential therapeutic targets in human pain. Emerging evidence suggests NaV1.6 channels are an important isoform in pain sensing. This study aimed to assess, using pharmacological approaches, the function of NaV1.6 channels in peripheral sensory neurons. The potent and NaV1.6 selective β‐scorpion toxin Cn2 was used to assess the effect of NaV1.6 channel activation in the PNS. The multidisciplinary approach included Ca2+ imaging, whole‐cell patch‐clamp recordings, skin–nerve and gut–nerve preparations and in vivo behavioural assessment of pain. Cn2 facilitates NaV1.6 early channel opening, and increased persistent and resurgent currents in large‐diameter dorsal root ganglion (DRG) neurons. This promotes enhanced excitatory drive and tonic action potential firing in these neurons. In addition, NaV1.6 channel activation in the skin and gut leads to increased response to mechanical stimuli. Finally, intra‐plantar injection of Cn2 causes mechanical but not thermal allodynia. This study confirms selectivity of Cn2 on NaV1.6 channels in sensory neurons. Activation of NaV1.6 channels, in terminals of the skin and viscera, leads to profound changes in neuronal responses to mechanical stimuli. In conclusion, sensory neurons expressing NaV1.6 are important for the transduction of mechanical information in sensory afferents innervating the skin and viscera.

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Section: Discussionmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

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Na_V1.6 regulates excitability of mechanosensitive sensory neurons

Israel

Tanaka

Castro

et al. 2019

The Journal of Physiology

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“…The alpha subunit is the functional and core subunit. Depending on the alpha subunit, voltage‐gated sodium channels can be classified into nine subtypes (NaV1.1‐NaV1.9) . The Nav1.7 alpha subunit is encoded by the SCN9A gene.…”

Section: Discussionmentioning

confidence: 99%

Voltage‐gated sodium channel 1.7 expression decreases in dorsal root ganglia in a spinal nerve ligation neuropathic pain model

Zhang

Yang

et al. 2019

The Kaohsiung J of Med Scie

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The role of the voltage-gated sodium channel 1.7 (Nav1.7) is unclear in models of neuropathic pain induced by nerve injury. In the present study, we measured expression levels of Nav1.7 in two distinct neuropathic pain models: spinal nerve ligation (SNL) and chronic constriction injury (CCI). In the SNL model, both mRNA and protein levels of Nav1.7 were markedly lower in the L5 dorsal root ganglia (DRG) but were significantly higher in the L4 DRG. Nav1.7 protein levels were notably higher in both L4 and L5 DRGs under CCI conditions. We found that excessive damage of L5 nerves such as SNL reduced expression levels of Nav1.7 in the injured L5 DRG and activated the adjacent uninjured DRG, resulting in Nav1.7 level increases in the adjacent L4 DRG. We confirmed again that Nav1.7 was closely related to neuropathic pain induced by nerve injury. More importantly, our results suggest that tracing the molecular changes exclusively in the L5 DRG in SNL model may not completely explain the pain mechanism; it is necessary to study the adjacent uninjured L4 DRG. K E Y W O R D S chronic constriction injury, dorsal root ganglia, neuropathic pain, spinal nerve ligation, voltagegated sodium channel 1.7

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“…Intriguingly, data (not included in this thesis) suggests the NaV1.6 isoform is important for excitability of peripheral neurons innervating the gut. Visceral afferents are solely comprised of small diameter thinly myelinated Aδ and non-myelinated C fibres (307)(308)(309)(310). However, single-cell RT-PCR data show that 62.5% of colon-innervating thoracolumbar DRG neurons express NaV1.6 channels (243).…”

Section: Discussionmentioning

confidence: 99%

Elucidating the role of NaV1.6 in peripheral sensory neurons

Israel¹

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Chronic pain is estimated to affect 1 in 5 Australians. The condition is debilitating for patients and remains a costly burden on the healthcare system. Analgesics currently in clinical use lack efficacy, have low tolerability and are hampered with wide side-effect profiles. Therefore, the underlying molecular mechanisms of pain sensing must be elucidated with a view to the development of improved therapeutics. Peripheral sensory neurons are the site of pain signal initiation and are critical for the detection of painful stimuli. Neuronal excitability relies on integral membrane bound proteins such as voltage-gated sodium channels (NaV), which allow the influx of sodium and action potential propagation in these cells. Nine different NaV subtypes have been identified (NaV1.1-1.9) of which a subset are expressed in peripheral sensory neurons. The exact role that each NaV isoform plays in the excitability of different fibre types remains unclear. This thesis uses a multidisciplinary approach to assess the role of the NaV subtype NaV1.6 in peripheral sensory neurons.NaV1.6 channels share high sequence homology with other NaV isoforms expressed in peripheral sensory neurons. Scorpion venom is a rich source of bioactive compounds, many of which act on mammalian NaV channels. One such peptide, Cn2, is reported to be a selective NaV1.6 activator. Chapter 2 describes the chemical synthesis of Cn2 using a strategy of native chemical ligation. The pharmacology of the synthetically derived Cn2 is in line with that of the venom derived peptide. This approach allows the development of a number of probes, including a novel NaV1.6 antagonist Cn2[E15R], that retain selectivity for NaV1.6. Therefore, this chapter characterises novel NaV1.6 selective compounds and provides insight into NaV1.6-toxin interactions.Peripheral sensory neurons express a range of different ion channels that are critical for their function. Chapter 3 aimed to assess the contribution of NaV1.6 to Na + currents in mouse isolated dorsal root ganglion cells. High-content calcium imaging and whole-cell patch clamp electrophysiology was performed using the selective Cn2 peptide as a probe for NaV1.6 function. Corresponding to expression of NaV1.6, Cn2 induces early Na + currents in large but not small diameter DRG neurons. The Cn2 effect is absent in NaV1.6 -/neurons confirming the selectivity of the peptide in a neuronal environment. Furthermore, Cn2 enhances excitability of large diameter neurons in vitro.

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Voltage‐gated sodium channels: (Na_V)igating the field to determine their contribution to visceral nociception

Cited by 38 publications

References 163 publications

Na_V1.6 regulates excitability of mechanosensitive sensory neurons

Na_V1.6 regulates excitability of mechanosensitive sensory neurons

Voltage‐gated sodium channel 1.7 expression decreases in dorsal root ganglia in a spinal nerve ligation neuropathic pain model

Elucidating the role of NaV1.6 in peripheral sensory neurons

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Voltage‐gated sodium channels: (NaV)igating the field to determine their contribution to visceral nociception

Cited by 38 publications

References 163 publications

NaV1.6 regulates excitability of mechanosensitive sensory neurons

NaV1.6 regulates excitability of mechanosensitive sensory neurons

Voltage‐gated sodium channel 1.7 expression decreases in dorsal root ganglia in a spinal nerve ligation neuropathic pain model

Elucidating the role of NaV1.6 in peripheral sensory neurons

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Voltage‐gated sodium channels: (Na_V)igating the field to determine their contribution to visceral nociception

Na_V1.6 regulates excitability of mechanosensitive sensory neurons

Na_V1.6 regulates excitability of mechanosensitive sensory neurons