A Novel Persistent Tetrodotoxin-Resistant Sodium Current In SNS-Null And Wild-Type Small Primary Sensory Neurons

Cummins, Theodore R.; Dib‐Hajj, Sulayman D.; Black, Joel A.; Akopian, Armen N.; Wood, John N.; Waxman, Stephen G.

doi:10.1523/jneurosci.19-24-j0001.1999

Cited by 417 publications

(425 citation statements)

References 25 publications

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“…As observed for Na v 1.8 mRNA, this was localized primarily over small to medium sized neurons representing 59.0% of all neurons analyzed, while only 13.9% of the neurons analyzed were large size neurons that express detectable levels of this message ( Figure 3; Table 2). These findings are consistent with those previously described (Black et al, 1996;Cummins et al, 1999;Dib-Hajj et al, 1999).…”

Section: Nt-3 Significantly Attenuates Neuronal Na V 18 Mrna Expressionsupporting

confidence: 94%

“…Consistent with previous reports (Akopian et al, 1996;Black et al, 1996;Cummins et al, 1999;Dib-Hajj et al, 1999), we found that expression is observed primarily in small to medium sized (<35 μm in diameter) neurons. These neurons represent 60.7% of all neurons analyzed, while only 9.6% were larger sized (>35 μm in diameter) neurons (Table 1).…”

Section: Nt-3 Significantly Attenuates Neuronal Na V 18 Mrna Expressionsupporting

confidence: 93%

“…They are associated with nociceptive neurons (Fang et al, 2002;Djourhi et al, 2003), and have been detected primarily in small diameter, but also in medium and large diameter DRG neurons (Akopian et al, 1996;Black et al, 1996;Rush et al, 1998;Cummins et al, 1999;Dib-Hajj et al, 1999;Renganathan et al, 2000;Hong and Wiley, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Neurotrophin-3 significantly reduces sodium channel expression linked to neuropathic pain states

Wilson-Gerwing

Stucky

McComb

et al. 2008

Experimental Neurology

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Neuropathic pain resulting from chronic constriction injury (CCI) is critically linked to sensitization of peripheral nociceptors. Voltage gated sodium channels are major contributors to this state and their expression can be upregulated by nerve growth factor (NGF). We have previously demonstrated that neurotrophin-3 (NT-3) acts antagonistically to NGF in modulation of aspects of CCI-induced changes in trkA-associated nociceptor phenotype and thermal hyperalgesia. Thus, we hypothesized that exposure of neurons to increased levels of NT-3 would reduce expression of Na v 1.8 and Na v 1.9 in DRG neurons subject to CCI. In adult male rats, Na v 1.8 and Na v 1.9 mRNAs are expressed at high levels in predominantly small to medium size neurons. One week following CCI, there is reduced incidence of neurons expressing detectable Na v 1.8 and Na v 1.9 mRNA, but without a significant decline in mean level of neuronal expression, and similar findings observed immunohistochemically. There is also increased accumulation/redistribution of channel protein in the nerve most apparent proximal to the first constriction site. Intrathecal infusion of NT-3 significantly attenuates neuronal expression of Na v 1.8 and Na v 1.9 mRNA contralateral and most notably, ipsilateral to CCI, with a similar impact on relative protein expression at the level of the neuron and constricted nerve. We also observe reduced expression of the common neurotrophin receptor p75 in response to CCI that is not reversed by NT-3 in small to medium sized neurons and may confer an enhanced ability of NT-3 to signal via trkA, as has been previously shown in other cell types. These findings are consistent with an analgesic role for NT-3.

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Section: Nt-3 Significantly Attenuates Neuronal Na V 18 Mrna Expressionsupporting

confidence: 94%

Section: Nt-3 Significantly Attenuates Neuronal Na V 18 Mrna Expressionsupporting

confidence: 93%

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Neurotrophin-3 significantly reduces sodium channel expression linked to neuropathic pain states

Wilson-Gerwing

Stucky

McComb

et al. 2008

Experimental Neurology

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“…The effect of FHF1B interaction with Na v 1.9 has yet to be determined. Na v 1.8 is a sensory neuron-specific sodium channel that produces a TTX-R current with different kinetic properties compared with Na v 1.5 and Na v 1.9 (42)(43)(44). Although Na v 1.5 and Na v 1.8 share ϳ80% amino acid identity in the CR1ϩCR2 region, Na v 1.8 failed to interact with FHF1B ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Modulation of the Cardiac Sodium Channel Nav1.5 by Fibroblast Growth Factor Homologous Factor 1B

Liu

Dib‐Hajj

Renganathan

et al. 2003

Journal of Biological Chemistry

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147

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We have previously shown that fibroblast growth factor homologous factor 1B (FHF1B), a cytosolic member of the fibroblast growth factor family, associates with the sensory neuron-specific channel Na v 1.9 but not with the other sodium channels present in adult rat dorsal root ganglia neurons. We show in this study that FHF1B binds to the C terminus of the cardiac voltage-gated sodium channel Na v 1.5 and modulates the properties of the channel. The N-terminal 41 amino acid residues of FHF1B are essential for binding to Na v 1.5, and the conserved acidic rich domain (amino acids 1773-1832) in the C terminus of Na v 1.5 is sufficient for association with this factor. Binding of the growth factor to recombinant wild type human Na v 1.5 in human embryonic kidney 293 cells produces a significant hyperpolarizing shift in the voltage dependence of channel inactivation. An aspartic acid to glycine substitution at position 1790 of the channel, which underlies one of the LQT-3 phenotypes of cardiac arrythmias, abolishes the interaction of the Na v 1.5 channel with FHF1B. This is the first report showing that interaction with a growth factor can modulate properties of a voltage-gated sodium channel.

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“…Increased I h could therefore contribute to spontaneous firing (Akasu et al, 1993), but its NGF dependence is unknown. A TTXR-persistent current in DRG neurons, activated around E m or at more hyperpolarized potentials, also tends to depolarize the membrane (Cummins et al, 1999). The NaN Na ϩ channel subunit, thought to be responsible for this current, is upregulated in DRG neurons in NGFoverexpressing mice (Fjell et al, 1999b) and thus may also be upregulated during inflammation.…”

Section: Possible Ionic Mechanismsmentioning

confidence: 99%

Time Course and Nerve Growth Factor Dependence of Inflammation-Induced Alterations in Electrophysiological Membrane Properties in Nociceptive Primary Afferent Neurons

et al. 2001

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Novel findings of changes in nociceptive dorsal root ganglion (DRG) neurons during hindlimb inflammation induced by complete Freund's adjuvant (CFA) injections in the hindpaw and hindleg are reported. These include increased maximum fiber following frequency in nociceptive C-and A␦-fiber units by 2.7 and 3 times, respectively, and increased incidence of ongoing (spontaneous) activity by 3.3 times (to 54%) and 2.4 times (to 27%), respectively. These changes and the CFA-induced changes in somatic action potential (AP) configuration in nociceptive neurons were incomplete 24 hr after CFA. The nerve growth factor (NGF) dependence of the inflammation-induced changes was examined by injecting a synthetic NGF sequestering protein [tyrosine receptor kinase A Ig2 (trkA Ig2)] with CFA and subsequently into the CFA injection sites. NGF sequestration prevented some CFA-induced changes in nociceptive neurons including: the increased fiber following frequency (C and A␦), the increased proportions of units with ongoing activity (C and A␦), the decreased AP duration (C and A␦), but not the decreased afterhyperpolarization (AHP) durations (C, A␦, and A␣/␤) . AP variables of nociceptive units with spontaneous activity were examined.The time course of electrophysiological changes in nociceptive units is consistent with processes involving altered protein expression and/or retrograde transport of factors. These results (1) implicate NGF in regulating inflammation-induced decreases in AP duration and in increases in firing rate and spontaneous activity but not in decreases in AHP duration and (2) suggest clinical advantages of reducing NGF in some inflammatory pain states. Key words: nociceptive neurons; DRG; hyperalgesia; NGF; firing rate; spontaneous activityInflammation is accompanied by hyperalgesia and allodynia. The underlying neuronal mechanisms are not fully understood, but short-term (hours) changes at more than one level of the nociceptive pathway occur, including sensitization of peripheral terminals and of central pathways (for review, see Millan, 1999). However, it is clear that longer term (days) changes in the electrical properties of the entire primary afferent neuron also occur during inflammation. These include decreased durations both of somatic action potentials (APs) in nociceptive C-and A␦-fiber units and of afterhyperpolarizations (AHPs) in nociceptive A␦ and A␣/␤-fiber neurons . The time course of these changes was not known.Nerve growth factor (NGF) is upregulated in inflamed tissues and transported back to the dorsal root ganglia (DRGs) (Woolf et al., 1994). NGF is implicated in mediating inflammatory hyperalgesia because (1) administration of NGF leads to hyperalgesia in adult rats (Lewin et al

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A Novel Persistent Tetrodotoxin-Resistant Sodium Current In SNS-Null And Wild-Type Small Primary Sensory Neurons

Cited by 417 publications

References 25 publications

Neurotrophin-3 significantly reduces sodium channel expression linked to neuropathic pain states

Neurotrophin-3 significantly reduces sodium channel expression linked to neuropathic pain states

Modulation of the Cardiac Sodium Channel Nav1.5 by Fibroblast Growth Factor Homologous Factor 1B

Time Course and Nerve Growth Factor Dependence of Inflammation-Induced Alterations in Electrophysiological Membrane Properties in Nociceptive Primary Afferent Neurons

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