Protein kinase C enhances human sodium channel hNav1.7 resurgent currents via a serine residue in the domain III–IV linker

Tan, ZC; Priest, Birgit T.; Krajewski, Jeffrey L.; Knopp, Kelly L.; Nisenbaum, Eric S.; Cummins, Theodore R.

doi:10.1016/j.febslet.2014.09.011

Cited by 19 publications

(19 citation statements)

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“…Protein kinase C (PKC) phosphorylation of Na V 1.7 exhibits a depolarizing effect on the voltage dependence of inactivation in some (Tan et al . ) but not all cell types (Vijayaragavan et al . ).…”

Section: Resultsmentioning

confidence: 99%

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Biphasic voltage‐dependent inactivation of human Na_V1.3, 1.6 and 1.7 Na⁺ channels expressed in rodent insulin‐secreting cells

Godazgar

Zhang

Chibalina

et al. 2018

The Journal of Physiology

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Key points Na+ current inactivation is biphasic in insulin‐secreting cells, proceeding with two voltage dependences that are half‐maximal at ∼−100 mV and −60 mV.Inactivation of voltage‐gated Na+ (NaV) channels occurs at ∼30 mV more negative voltages in insulin‐secreting Ins1 and primary β‐cells than in HEK, CHO or glucagon‐secreting αTC1‐6 cells.The difference in inactivation between Ins1 and non‐β‐cells persists in the inside‐out patch configuration, discounting an involvement of a diffusible factor.In Ins1 cells and primary β‐cells, but not in HEK cells, inactivation of a single NaV subtype is biphasic and follows two voltage dependences separated by 30–40 mV.We propose that NaV channels adopt different inactivation behaviours depending on the local membrane environment. AbstractPancreatic β‐cells are equipped with voltage‐gated Na+ channels that undergo biphasic voltage‐dependent steady‐state inactivation. A small Na+ current component (10–15%) inactivates over physiological membrane potentials and contributes to action potential firing. However, the major Na+ channel component is completely inactivated at −90 to −80 mV and is therefore inactive in the β‐cell. It has been proposed that the biphasic inactivation reflects the contribution of different NaV α‐subunits. We tested this possibility by expression of TTX‐resistant variants of the NaV subunits found in β‐cells (NaV1.3, NaV1.6 and NaV1.7) in insulin‐secreting Ins1 cells and in non‐β‐cells (including HEK and CHO cells). We found that all NaV subunits inactivated at 20–30 mV more negative membrane potentials in Ins1 cells than in HEK or CHO cells. The more negative inactivation in Ins1 cells does not involve a diffusible intracellular factor because the difference between Ins1 and CHO persisted after excision of the membrane. NaV1.7 inactivated at 15‐20 mV more negative membrane potentials than NaV1.3 and NaV1.6 in Ins1 cells but this small difference is insufficient to solely explain the biphasic inactivation in Ins1 cells. In Ins1 cells, but never in the other cell types, widely different components of NaV inactivation (separated by 30 mV) were also observed following expression of a single type of NaV α‐subunit. The more positive component exhibited a voltage dependence of inactivation similar to that found in HEK and CHO cells. We propose that biphasic NaV inactivation in insulin‐secreting cells reflects insertion of channels in membrane domains that differ with regard to lipid and/or membrane protein composition.

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Section: Resultsmentioning

confidence: 99%

“…Protein kinase C (PKC) phosphorylation of Na V 1.7 exhibits a depolarizing effect on the voltage dependence of inactivation in some (Tan et al 2014) but not all cell types (Vijayaragavan et al 2004). Moreover, Na V 1.3 and Na V 1.6 contain a putative PKC phosphorylation site in the same L3 region.…”

Section: Modulation Of Inactivationmentioning

confidence: 99%

Biphasic voltage‐dependent inactivation of human Na_V1.3, 1.6 and 1.7 Na⁺ channels expressed in rodent insulin‐secreting cells

Godazgar

Zhang

Chibalina

et al. 2018

The Journal of Physiology

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“…Nav1.7 is able to generate TTXS resurgent sodium currents in sensory neurons [ 15 ]. Wild-type Nav1.7 is not an efficient generator of resurgent sodium currents [ 15 ] despite having similar kinetics of open-state inactivation to Nav1.6 [ 67 ], but mutations identified in patients with Paroxysmal Extreme Pain Disorder can substantially increase Nav1.7 resurgent currents [ 15 , 44 , 68 ]. Nav1.8 channels can also generate resurgent sodium currents in DRG sensory neurons [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, an inflammatory soup applied to cultured DRG neurons increased both TTXS and TTXR resurgent currents, suggesting that resurgent currents can also play a role in inflammatory pain [ 40 ]. Inflammatory mediators can increase the activity of multiple kinases and phosphorylation is known to enhance resurgent current generation [ 68 , 69 ]. It will be interesting to determine if chronic oxaliplatin treatment and/or chronic inflammation can induce an upregulation of Navβ4 in sensory neurons.…”

Section: Discussionmentioning

confidence: 99%

Navβ4 Regulates Fast Resurgent Sodium Currents and Excitability in Sensory Neurons

et al. 2015

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BackgroundIncreased electrical activity in peripheral sensory neurons including dorsal root ganglia (DRG) and trigeminal ganglia neurons is an important mechanism underlying pain. Voltage gated sodium channels (VGSC) contribute to the excitability of sensory neurons and are essential for the upstroke of action potentials. A unique type of VGSC current, resurgent current (INaR), generates an inward current at repolarizing voltages through an alternate mechanism of inactivation referred to as open-channel block. INaRs are proposed to enable high frequency firing and increased INaRs in sensory neurons are associated with pain pathologies. While Nav1.6 has been identified as the main carrier of fast INaR, our understanding of the mechanisms that contribute to INaR generation is limited. Specifically, the open-channel blocker in sensory neurons has not been identified. Previous studies suggest Navβ4 subunit mediates INaR in central nervous system neurons. The goal of this study was to determine whether Navβ4 regulates INaR in DRG sensory neurons.ResultsOur immunocytochemistry studies show that Navβ4 expression is highly correlated with Nav1.6 expression predominantly in medium-large diameter rat DRG neurons. Navβ4 knockdown decreased endogenous fast INaR in medium-large diameter neurons as measured with whole-cell voltage clamp. Using a reduced expression system in DRG neurons, we isolated recombinant human Nav1.6 sodium currents in rat DRG neurons and found that overexpression of Navβ4 enhanced Nav1.6 INaR generation. By contrast neither overexpression of Navβ2 nor overexpression of a Navβ4-mutant, predicted to be an inactive form of Navβ4, enhanced Nav1.6 INaR generation. DRG neurons transfected with wild-type Navβ4 exhibited increased excitability with increases in both spontaneous activity and evoked activity. Thus, Navβ4 overexpression enhanced INaR and excitability, whereas knockdown or expression of mutant Navβ4 decreased INaR generation.ConclusionINaRs are associated with inherited and acquired pain disorders. However, our ability to selectively target and study this current has been hindered due to limited understanding of how it is generated in sensory neurons. This study identified Navβ4 as an important regulator of INaR and excitability in sensory neurons. As such, Navβ4 is a potential target for the manipulation of pain sensations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12990-015-0063-9) contains supplementary material, which is available to authorized users.

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“…In carrageenan-induced muscle inflammation, enhanced responses of group III nociceptors innervating the gastrocnemius muscle are readily blocked by TTX at time points as early as 1-1.5 hr after carrageenan injection (Schomburg et al, 2012). In this context, several inflammatory mediators signal through protein kinase C (PKC), which is known to enhance TTX-S sodium channel resurgent currents (Tan et al, 2014). Besides, tumor necrosis factor alpha, is produced at the site of carrageenan inflammation and signals through extracellular-regulated kinases (ERK) (Utreras et al, 2009), which phosphorylates Nav1.7 in DRG neurons (Stamboulian et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Antihyperalgesic effect of tetrodotoxin in rat models of persistent muscle pain

Álvarez

Levine

2015

Neuroscience

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Persistent muscle pain is a common and disabling symptom for which available treatments have limited efficacy. Since tetrodotoxin (TTX) displays a marked antinociceptive effect in models of persistent cutaneous pain, we tested its local antinociceptive effect in rat models of muscle pain induced by inflammation, ergonomic injury and chemotherapy-induced neuropathy. While local injection of TTX (0.03-1 μg) into the gastrocnemius muscle did not affect mechanical nociceptive threshold in naïve rats, exposure to the inflammogen carrageenan produced a marked muscle mechanical hyperalgesia, which was dose-dependently inhibited by TTX. This antihyperalgesic effect was still significant at 24 hours. TTX also displayed a robust antinociceptive effect on eccentric exercise-induced mechanical hyperalgesia in the gastrocnemius muscle, a model of ergonomic pain. Finally, TTX produced a small but significant inhibition of neuropathic muscle pain induced by systemic administration of the cancer chemotherapeutic agent oxaliplatin. These results indicate that TTX-sensitive sodium currents in nociceptors play a central role in diverse states of skeletal muscle nociceptive sensitization, supporting the suggestion that therapeutic interventions based on TTX may prove useful in the treatment of muscle pain.

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Protein kinase C enhances human sodium channel hNav1.7 resurgent currents via a serine residue in the domain III–IV linker

Cited by 19 publications

References 28 publications

Biphasic voltage‐dependent inactivation of human Na_V1.3, 1.6 and 1.7 Na⁺ channels expressed in rodent insulin‐secreting cells

Biphasic voltage‐dependent inactivation of human Na_V1.3, 1.6 and 1.7 Na⁺ channels expressed in rodent insulin‐secreting cells

Navβ4 Regulates Fast Resurgent Sodium Currents and Excitability in Sensory Neurons

Antihyperalgesic effect of tetrodotoxin in rat models of persistent muscle pain

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Protein kinase C enhances human sodium channel hNav1.7 resurgent currents via a serine residue in the domain III–IV linker

Cited by 19 publications

References 28 publications

Biphasic voltage‐dependent inactivation of human NaV1.3, 1.6 and 1.7 Na+ channels expressed in rodent insulin‐secreting cells

Biphasic voltage‐dependent inactivation of human NaV1.3, 1.6 and 1.7 Na+ channels expressed in rodent insulin‐secreting cells

Navβ4 Regulates Fast Resurgent Sodium Currents and Excitability in Sensory Neurons

Antihyperalgesic effect of tetrodotoxin in rat models of persistent muscle pain

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Biphasic voltage‐dependent inactivation of human Na_V1.3, 1.6 and 1.7 Na⁺ channels expressed in rodent insulin‐secreting cells

Biphasic voltage‐dependent inactivation of human Na_V1.3, 1.6 and 1.7 Na⁺ channels expressed in rodent insulin‐secreting cells