Increased Resurgent Sodium Currents in Nav1.8 Contribute to Nociceptive Sensory Neuron Hyperexcitability Associated with Peripheral Neuropathies

dc.contributor.authorXiao, Yucheng
dc.contributor.authorBarbosa, Cindy
dc.contributor.authorPei, Zifan
dc.contributor.authorXie, Wenrui
dc.contributor.authorStrong, Judith A.
dc.contributor.authorZhang, Jun-Ming
dc.contributor.authorCummins, Theodore R.
dc.contributor.departmentBiology, School of Scienceen_US
dc.date.accessioned2019-10-16T20:04:05Z
dc.date.available2019-10-16T20:04:05Z
dc.date.issued2019-02-20
dc.description.abstractNeuropathic pain is a significant public health challenge, yet the underlying mechanisms remain poorly understood. Painful small fiber neuropathy (SFN) may be caused by gain-of-function mutations in Nav1.8, a sodium channel subtype predominantly expressed in peripheral nociceptive neurons. However, it is not clear how Nav1.8 disease mutations induce sensory neuron hyperexcitability. Here we studied two mutations in Nav1.8 associated with hypersensitive sensory neurons: G1662S reported in painful SFN; and T790A, which underlies increased pain behaviors in the Possum transgenic mouse strain. We show that, in male DRG neurons, these mutations, which impair inactivation, significantly increase TTX-resistant resurgent sodium currents mediated by Nav1.8. The G1662S mutation doubled resurgent currents, and the T790A mutation increased them fourfold. These unusual currents are typically evoked during the repolarization phase of action potentials. We show that the T790A mutation greatly enhances DRG neuron excitability by reducing current threshold and increasing firing frequency. Interestingly, the mutation endows DRG neurons with multiple early afterdepolarizations and leads to substantial prolongation of action potential duration. In DRG neurons, siRNA knockdown of sodium channel β4 subunits fails to significantly alter T790A current density but reduces TTX-resistant resurgent currents by 56%. Furthermore, DRG neurons expressing T790A channels exhibited reduced excitability with fewer early afterdepolarizations and narrower action potentials after β4 knockdown. Together, our data demonstrate that open-channel block of TTX-resistant currents, enhanced by gain-of-function mutations in Nav1.8, can make major contributions to the hyperexcitability of nociceptive neurons, likely leading to altered sensory phenotypes including neuropathic pain in SFN.SIGNIFICANCE STATEMENT This work demonstrates that two disease mutations in the voltage-gated sodium channel Nav1.8 that induce nociceptor hyperexcitability increase resurgent currents. Nav1.8 is crucial for pain sensations. Because resurgent currents are evoked during action potential repolarization, they can be crucial regulators of action potential activity. Our data indicate that increased Nav1.8 resurgent currents in DRG neurons greatly prolong action potential duration and enhance repetitive firing. We propose that Nav1.8 open-channel block is a major factor in Nav1.8-associated pain mechanisms and that targeting the molecular mechanism underlying these unique resurgent currents represents a novel therapeutic target for the treatment of aberrant pain sensations.en_US
dc.identifier.citationXiao, Y., Barbosa, C., Pei, Z., Xie, W., Strong, J. A., Zhang, J. M., & Cummins, T. R. (2019). Increased Resurgent Sodium Currents in Nav1.8 Contribute to Nociceptive Sensory Neuron Hyperexcitability Associated with Peripheral Neuropathies. The Journal of neuroscience : the official journal of the Society for Neuroscience, 39(8), 1539–1550. doi:10.1523/JNEUROSCI.0468-18.2018en_US
dc.identifier.urihttps://hdl.handle.net/1805/21177
dc.language.isoen_USen_US
dc.publisherSociety for Neuroscienceen_US
dc.relation.isversionof10.1523/JNEUROSCI.0468-18.2018en_US
dc.relation.journalThe Journal of Neuroscienceen_US
dc.rightsPublisher Policyen_US
dc.sourcePMCen_US
dc.subjectBeta subuniten_US
dc.subjectHyperexcitabilityen_US
dc.subjectPainen_US
dc.subjectResurgenten_US
dc.subjectSodium channelen_US
dc.titleIncreased Resurgent Sodium Currents in Nav1.8 Contribute to Nociceptive Sensory Neuron Hyperexcitability Associated with Peripheral Neuropathiesen_US
dc.typeArticleen_US
ul.alternative.fulltexthttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381260/en_US
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