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

Cindy Barbosa, Yucheng Xiao, Andrew J. Johnson, Wenrui Xie, Judith A. Strong, Jun Ming Zhang, Theodore Cummins

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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 that 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.

Original languageEnglish (US)
Pages (from-to)195-212
Number of pages18
JournalPflugers Archiv European Journal of Physiology
Volume469
Issue number2
DOIs
StatePublished - Feb 1 2017

Fingerprint

Spinal Ganglia
Sensory Receptor Cells
Neurons
Protein Isoforms
Sodium
Pain
Pathology
Aptitude
Fibroblast Growth Factors
Cell Line
Peptides
Cells
Recovery
Proteins

Keywords

  • Dorsal root ganglia neurons
  • FHF
  • Fibroblast growth factor homologous factor
  • Resurgent current
  • Resurgent Na+ current

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)

Cite this

FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons. / Barbosa, Cindy; Xiao, Yucheng; Johnson, Andrew J.; Xie, Wenrui; Strong, Judith A.; Zhang, Jun Ming; Cummins, Theodore.

In: Pflugers Archiv European Journal of Physiology, Vol. 469, No. 2, 01.02.2017, p. 195-212.

Research output: Contribution to journalArticle

Barbosa, Cindy ; Xiao, Yucheng ; Johnson, Andrew J. ; Xie, Wenrui ; Strong, Judith A. ; Zhang, Jun Ming ; Cummins, Theodore. / FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons. In: Pflugers Archiv European Journal of Physiology. 2017 ; Vol. 469, No. 2. pp. 195-212.
@article{271216fe530a48549504233474510e0f,
title = "FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons",
abstract = "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 that 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.",
keywords = "Dorsal root ganglia neurons, FHF, Fibroblast growth factor homologous factor, Resurgent current, Resurgent Na+ current",
author = "Cindy Barbosa and Yucheng Xiao and Johnson, {Andrew J.} and Wenrui Xie and Strong, {Judith A.} and Zhang, {Jun Ming} and Theodore Cummins",
year = "2017",
month = "2",
day = "1",
doi = "10.1007/s00424-016-1911-9",
language = "English (US)",
volume = "469",
pages = "195--212",
journal = "Pflugers Archiv European Journal of Physiology",
issn = "0031-6768",
publisher = "Springer Verlag",
number = "2",

}

TY - JOUR

T1 - FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons

AU - Barbosa, Cindy

AU - Xiao, Yucheng

AU - Johnson, Andrew J.

AU - Xie, Wenrui

AU - Strong, Judith A.

AU - Zhang, Jun Ming

AU - Cummins, Theodore

PY - 2017/2/1

Y1 - 2017/2/1

N2 - 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 that 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.

AB - 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 that 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.

KW - Dorsal root ganglia neurons

KW - FHF

KW - Fibroblast growth factor homologous factor

KW - Resurgent current

KW - Resurgent Na+ current

UR - http://www.scopus.com/inward/record.url?scp=85006826060&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85006826060&partnerID=8YFLogxK

U2 - 10.1007/s00424-016-1911-9

DO - 10.1007/s00424-016-1911-9

M3 - Article

C2 - 27999940

AN - SCOPUS:85006826060

VL - 469

SP - 195

EP - 212

JO - Pflugers Archiv European Journal of Physiology

JF - Pflugers Archiv European Journal of Physiology

SN - 0031-6768

IS - 2

ER -