Alternative splicing of NaV1.7 exon 5 increases the impact of the painful PEPD mutant channel I1461T

Brian W. Jarecki, Patrick L. Sheets, Yucheng Xiao, James O. Jackson, Theodore R. Cummins

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Alternative splicing is known to alter pharmacological sensitivities, kinetics, channel distribution under pathological conditions, and developmental regulation of VGsCs. Mutations that alter channel properties in Na V1.7 have been genetically implicated in patients with bouts of extreme pain classified as inherited erythromelalgia (IEM) or paroxysmal extreme pain disorder (PEPD). Furthermore, patients with IEM or PEPD report differential age onsets. A recent study reported that alternative splicing of NaV1.7 exon 5 affects ramp current properties. since IeM and PEPD mutations also alter NaV1.7 ramp current properties we speculated that alternative splicing might impact the functional consequences of IeM or PEPD mutations. We compared the effects alternative splicing has on the biophysical properties of NaV1.7 wild-type, IEM (I136V) and PEPD (I1461T) channels. Our major findings demonstrate that although the 5A splice variant of the IEM channel had no functional impact, the 5A splice variant of the PEPD channel significantly hyperpolarized the activation curve, slowed deactivation and closed-state inactivation, shifted the ramp current activation to more hyperpolarized potentials, and increased ramp current amplitude. We hypothesize a D1/S3-S4 charged residue difference between the 5N (Asn) and the 5A (Asp) variants within the coding region of exon 5 may contribute to shifts in channel activation and deactivation. Taken together, the additive effects observed on ramp currents from exon 5 splicing and the PEPD mutation (I1461T) are likely to impact the disease phenotype and may offer insight into how alternative splicing may affect specific intramolecular interactions critical for voltage-dependent gating.

Original languageEnglish (US)
JournalChannels
Volume3
Issue number4
DOIs
StatePublished - Jan 1 2009

Fingerprint

Alternative Splicing
Architectural Accessibility
Exons
Erythromelalgia
Chemical activation
Mutation
Viperidae
Paroxysmal Extreme Pain Disorder
Age of Onset
Kinetics
Electric potential
Pharmacology
Phenotype
Pain

Keywords

  • Alternative splicing
  • Electrophysiology
  • Erythromelalgia
  • Na1.7
  • Paroxysmal extreme pain disorder
  • Sodium channels

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry

Cite this

Alternative splicing of NaV1.7 exon 5 increases the impact of the painful PEPD mutant channel I1461T. / Jarecki, Brian W.; Sheets, Patrick L.; Xiao, Yucheng; Jackson, James O.; Cummins, Theodore R.

In: Channels, Vol. 3, No. 4, 01.01.2009.

Research output: Contribution to journalArticle

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abstract = "Alternative splicing is known to alter pharmacological sensitivities, kinetics, channel distribution under pathological conditions, and developmental regulation of VGsCs. Mutations that alter channel properties in Na V1.7 have been genetically implicated in patients with bouts of extreme pain classified as inherited erythromelalgia (IEM) or paroxysmal extreme pain disorder (PEPD). Furthermore, patients with IEM or PEPD report differential age onsets. A recent study reported that alternative splicing of NaV1.7 exon 5 affects ramp current properties. since IeM and PEPD mutations also alter NaV1.7 ramp current properties we speculated that alternative splicing might impact the functional consequences of IeM or PEPD mutations. We compared the effects alternative splicing has on the biophysical properties of NaV1.7 wild-type, IEM (I136V) and PEPD (I1461T) channels. Our major findings demonstrate that although the 5A splice variant of the IEM channel had no functional impact, the 5A splice variant of the PEPD channel significantly hyperpolarized the activation curve, slowed deactivation and closed-state inactivation, shifted the ramp current activation to more hyperpolarized potentials, and increased ramp current amplitude. We hypothesize a D1/S3-S4 charged residue difference between the 5N (Asn) and the 5A (Asp) variants within the coding region of exon 5 may contribute to shifts in channel activation and deactivation. Taken together, the additive effects observed on ramp currents from exon 5 splicing and the PEPD mutation (I1461T) are likely to impact the disease phenotype and may offer insight into how alternative splicing may affect specific intramolecular interactions critical for voltage-dependent gating.",
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