ERK1/2 Mitogen-Activated Protein Kinase Phosphorylates Sodium Channel Na(v)1.7 and Alters Its Gating Properties

Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 02/2010; 30(5):1637-47. DOI: 10.1523/JNEUROSCI.4872-09.2010
Source: PubMed


Na(v)1.7 sodium channels can amplify weak stimuli in neurons and act as threshold channels for firing action potentials. Neurotrophic factors and pro-nociceptive cytokines that are released during development and under pathological conditions activate mitogen-activated protein kinases (MAPKs). Previous studies have shown that MAPKs can transduce developmental or pathological signals by regulating transcription factors that initiate a gene expression response, a long-term effect, and directly modulate neuronal ion channels including sodium channels, thus acutely regulating dorsal root ganglion (DRG) neuron excitability. For example, neurotrophic growth factor activates (phosphorylates) ERK1/2 MAPK (pERK1/2) in DRG neurons, an effect that has been implicated in injury-induced hyperalgesia. However, the acute effects of pERK1/2 on sodium channels are not known. We have shown previously that activated p38 MAPK (pp38) directly phosphorylates Na(v)1.6 and Na(v)1.8 sodium channels and regulates their current densities without altering their gating properties. We now report that acute inhibition of pERK1/2 regulates resting membrane potential and firing properties of DRG neurons. We also show that pERK1 phosphorylates specific residues within L1 of Na(v)1.7, inhibition of pERK1/2 causes a depolarizing shift of activation and fast inactivation of Na(v)1.7 without altering current density, and mutation of these L1 phosphoacceptor sites abrogates the effect of pERK1/2 on this channel. Together, these data are consistent with direct phosphorylation and modulation of Na(v)1.7 by pERK1/2, which unlike the modulation of Na(v)1.6 and Na(v)1.8 by pp38, regulates gating properties of this channel but not its current density and contributes to the effects of MAPKs on DRG neuron excitability.

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    • "It would be interesting to test if other protein kinases contribute to the enhancing effects of inflammatory mediators on resurgent currents in DRG neurons. For example, ERK1/2 activation was found to directly phosphorylate Nav1.7 and an ERK1/2 inhibitor caused a depolarizing shift in the activation curve of Nav1.7 and decreased excitability of DRG neurons [19]. Three conserved PKC phosphorylation sites in sodium channels have been reported [28] [3]. "
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    • "The expression of the high-affinity NGF receptor TrkA in adult DRG is restricted to nociceptors [8]. After NGF binds to TrkA on nociceptors, mitogen-activated protein kinases are activated [17] and then phosphorylate voltage-gated sodium channels to make nociceptors hyperexcitable without de novo protein synthesis [19] [50]. NGF, as well as other neurotrophins, did not significantly alter the number of TrkA(+) DRG neurons at day 3 after intrathecal injection to naive rats [35]. "
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    • "Retrograde transport of NGF via the peripheral terminals of abnormally sprouting sensory nerve fibres to the cell bodies of primary sensory neurons in the dorsal root ganglia (DRGs) likely contributes to first-order sensory neuron hyperexcitability via multiple mechanisms. Such mechanisms include upregulated synthesis of pro-nociceptive mediators (Mantyh et al. 2011), activation of p38 mitogenactivated protein kinase (MAPK) (Ji et al. 2002) and p44/ p42 MAPK (Averill et al. 2001)-induced sensitization (phosphorylation) of the TRPV1 (Ji et al. 2002) as well as voltage-gated sodium (Hudmon et al. 2008; Stamboulian et al. 2010) and calcium channels (Martin et al. 2006). Together, these observations strongly implicate a role for NGF/TrkA signalling in the maintenance of PCIBP. "
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