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Research Paper

Alternative splicing of Na_V1.7 exon 5 increases the impact of the painful PEPD mutant channel I1461T

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

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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 Na_V1.7 exon 5 affects ramp current properties. Since IEM and PEPD mutations also alter Na_V1.7 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 Na_V1.7 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.

Authors

Brian W. Jarecki

Indiana University School of Medicine; Stark Neurosciences Research Institute; Indianapolis, IN USA

Patrick L. Sheets

Northwestern University; Feinberg School of Medicine; Chicago, IL USA

Yucheng Xiao

Indiana University School of Medicine; Stark Neurosciences Research Institute; Indianapolis, IN USA

James O. Jackson

Indiana University School of Medicine; Stark Neurosciences Research Institute; Indianapolis, IN USA

Theodore R. Cummins Corresponding author: trcummin@iupui.edu

Indiana University School of Medicine; Stark Neurosciences Research Institute; Indianapolis, IN USA

This is an open-access article

 Download PDF

If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.