The pentapeptide QYNAD does not block voltage-gated sodium channels

Cummins, Theodore R.; Renganathan, Muthukrishnan; Stys, Peter K.; Herzog, Raimund I.; Scarfo, Keith; Horn, Richard; Dib‐Hajj, Sulayman D.; Waxman, S. G.

doi:10.1212/01.wnl.0000042423.36650.bd

Cited by 26 publications

(22 citation statements)

References 27 publications

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“…Although endogenous TTXR Nav1.8 channels run down in culture (17, 28), by using the Nav1.8 shRNA-IRES-dsRED plasmid we further decreased Nav1.8 to minimize contamination. TTXR Nav1.9 currents are not observed under our recoding parameters as previously reported (7, 11). Endogenous TTXS channels were blocked with 500nM.…”

Section: Methodssupporting

confidence: 85%

FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons

Barbosa

Xiao

Johnson

et al. 2016

Pflugers Arch - Eur J Physiol

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Nav1.6 and Nav1.6 mediated resurgent currents have been implicated in several pain pathologies. However, our knowledge of how fast resurgent currents are modulated in neurons is limited. Our study explored the potential regulation of Nav1.6 mediated resurgent currents by isoforms of Fibroblast growth Factor Homologous factor 2 (FHF2) in an effort to address the gap in our knowledge. FHF2 isoforms colocalize with Nav1.6 in peripheral sensory neurons. Cell line studies suggest that these proteins differentially regulate inactivation. In particular, FHF2A mediates long-term inactivation, a mechanism proposed to compete with the open-channel blocker mechanism that mediates resurgent currents. On the other hand, FHF2B lacks the ability to mediate long-term inactivation and may delay inactivation favoring open-channel block. Based on these observations, we hypothesized that FHF2A limits resurgent currents, whereas, FHF2B enhances resurgent currents. Overall our results suggest that FHF2A negatively regulates fast resurgent current by enhancing long-term inactivation and delaying recovery. In contrast FHF2B positively regulated resurgent current and did not alter long-term inactivation. Chimeric constructs of FHF2A and Navβ4 (likely the endogenous open channel blocker in sensory neurons) exhibited differential effects on resurgent currents suggesting that specific regions within FHF2A and Navβ4 have important regulatory functions. Our data also indicate FHFAs and FHF2B isoform expression are differentially regulated in a radicular pain model and that associated neuronal hyperexcitability is substantially attenuated by a FHFA peptide. As such, these findings suggest that FHF2A and FHF2B regulate resurgent current in sensory neurons and may contribute to hyperexcitability associated with some pain pathologies.

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Section: Methodssupporting

confidence: 85%

FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons

Barbosa

Xiao

Johnson

et al. 2016

Pflugers Arch - Eur J Physiol

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“…While Cummins et al [6] conclude that the purported blocking action of QYNAD should be viewed with caution, our findings corroborate the earlier observations of Brinkmeier et al [3]. In our hands the QYNAD-related effects on voltage-gated sodium channels were observed upon sufficient equilibration of the peptide in the external bath solution, and by holding the membrane at hyperpolarized potentials for at least 3 min before the voltage protocols were applied after stabilization of the membrane seal.…”

Section: Discussionsupporting

confidence: 91%

“…We observed that proper equilibration of the peptide in the bath was essential before we could proceed with the experimental protocols. In the recent report by Cummins et al [6] the voltage dependence of activation and steady-state inactivation were measured after exposure to QYNAD for 1.5-2 min. Our earlier attempts with the peptide without equilibration failed to show the changes in the voltage dependence characteristics or the frequencydependent block reported here.…”

Section: Discussionmentioning

confidence: 99%

“…However, the NMR evidence for the presence of the N-terminally blocked peptide is unambiguous. Waxman and co-workers [6] used both the free and Nterminally acylated QYNAD in their studies. It has been reported that acylation of the N-terminal amino group of QYNAD did not significantly affect the voltage-gated sodium channel blocking activity [3].…”

Section: Mass Spectrometrymentioning

confidence: 99%

“…The amplitude and the area of the compound nerve action potential were found to decrease by 30-40% while the latency was found to increase in isolated rat sciatic nerve subjected to 100 μM QYNAD [33]. Recently the effects of QYNAD have been re-examined on several sodium channel isoforms in mammalian cells and on native sodium channels, including axonal conduction [6]. Their findings are contrary to those reported by Brinkmeier et al [3], and suggest that voltage-gated sodium channels are not blocked by QYNAD.…”

Section: Introductionmentioning

confidence: 99%

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Functional characterization of the pentapeptide QYNAD on rNa v 1.2 channels and its NMR structure

Padmashri

Chakrabarti

Sahal

et al. 2004

Pfl�gers Archiv European Journal of Physiology

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The endogenous pentapeptide QYNAD (Gln-Tyr-Asn-Ala-Asp) is present in human cerebrospinal fluid (CSF), and its concentration is increased in demyelinating diseases. QYNAD was synthesized and its action on the rNav1.2 voltage-gated sodium channel alpha-subunit was studied using whole-cell recordings in a heterologous expression system. The effects were seen only upon equilibration of the peptide in the external bath solution for at least 10 min before the commencement of whole-cell experiments. The steady-state activation curve showed a rightward shift of 10 mV, while the steady-state inactivation curve showed a leftward shift of 5 mV. Frequency-dependent inhibition of the sodium current amplitude was observed at 2-10 Hz, in the presence of external QYNAD, but was not seen when applied internally. Fits of the whole-cell sodium current traces by Hodgkin-Huxley equations revealed subtle changes in the voltage-dependent rate constants governing the transition of the activation and the inactivation gates. Two dimensional NMR spectroscopy revealed the absence of medium and long-range Nuclear Overhauser effects (NOEs), which indicates that the peptide does not adopt any canonical secondary structure in solution. In summary, our studies show that although the pentapeptide QYNAD does not have a defined structure in solution, it has defined actions on the rNav1.2 voltage-gated sodium channel isoform.

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Pharmacological treatment other than corticosteroids, intravenous immunoglobulin and plasma exchange for Guillain Barré syndrome

Hughes

Pritchard

Hadden

2011

Cochrane Database of Systematic Reviews

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The pentapeptide QYNAD does not block voltage-gated sodium channels

Abstract: These experiments do not show any sodium channel blocking effect of QYNAD. The conclusion that QYNAD contributes to the pathophysiology of inflammatory neurologic disorders by blocking voltage-gated sodium channels should therefore be viewed with caution.

Cited by 26 publications

References 27 publications

FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons

FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons

Functional characterization of the pentapeptide QYNAD on rNa v 1.2 channels and its NMR structure

Pharmacological treatment other than corticosteroids, intravenous immunoglobulin and plasma exchange for Guillain Barré syndrome

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