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The Journal of physiology1996; 497 ( Pt 2)(Pt 2); 349-364; doi: 10.1113/jphysiol.1996.sp021773

The equine periodic paralysis Na+ channel mutation alters molecular transitions between the open and inactivated states.

Abstract: 1. The Na+ channel mutation associated with equine hyperkalaemic periodic paralysis (HPP) affects a highly conserved phenylalanine residue in an unexplored region of the alpha-subunit. This mutation was introduced into the rat skeletal muscle Na+ channel gene at the corresponding location (i.e. F1412L) for functional expression and characterization in Xenopus oocytes. 2. In comparison with wild-type (WT) channels, equine HPP channels showed clear evidence for disruption of inactivation: increased time-to-peak current, slowed rates of whole-cell current decay, significant increases in sustained current, rightward shifts in the steady-state inactivation curve by 9.5 mV, a 6-fold acceleration in the rate of recovery from inactivation at -80 mV, decreased number of blank single-channel sweeps, repetitive opening of single channels throughout depolarizing steps, increased open probability per sweep, and an increased mean open time. 3. The observed disruption of inactivation in HPP occurred without measurable changes in steady-state activation and first latency kinetics of channel opening. 4. Kinetic modelling demonstrates that the equine HPP phenotype can be simulated by altering the rate constants for transitions entering and leaving the inactivated states resulting from an energetic destabilization of the inactivated state. 5. These results suggest that the highly conserved cytoplasmic end of the third transmembrane segment (S3) in the fourth internal repeat domain (domain IV) plays a critical role in Na+ channel inactivation.
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Publication Date: 1996-12-01 PubMed ID: 8961180PubMed Central: PMC1160989DOI: 10.1113/jphysiol.1996.sp021773Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research article investigates how a specific sodium channel mutation connected to equine hyperkalaemic periodic paralysis (HPP) disrupts the inactivation process of the sodium channel in horses, thereby leading to paralysis.

Overview and Methodology

  • The research concentrates on a specific mutation in the alpha-subunit of the sodium channel found in horses suffering from hyperkalaemic periodic paralysis (HPP), a muscular disease affecting the functionality of skeletal muscles.
  • Scientists emulated this mutation (F1412L) in the rat skeletal muscle sodium channel gene and observed its effects in Xenopus oocytes — a kind of frog egg used commonly in biological studies because of their large size and ease of manipulation.

Mutation Effects

  • Comparing the mutated HPP channels with normal, or wild-type (WT) channels, the researchers observed disruptions in the inactivation process – the period in ion channels’ working where they shut off the ions’ flow.
  • Disruptions included prolonged time-to-peak current, slowed decay rates, increased sustained current, altered inactivation curve, accelerated recovery from inactivation, decreased number of blank single-channel sweeps, repeated single channel opening throughout voltage steps, increased open probability per sweep, and lengthened mean open time.
  • These changes happened with no noticeable variations in steady-state activation and the first latency kinetics – the speed of reaction on the first response.

Kinetic Modeling and Inference

  • Using kinetic modeling, the researchers illustrated that the equine HPP phenotype – observable traits due to the mutation, can be mimicked by modifying rate constants for transitions entering and leaving the inactivated states due to an energetic destabilization of the inactivated state.
  • This indicates that the highly conserved cytoplasmic end of the third transmembrane segment (S3) in the fourth internal repeat domain (domain IV) has a crucial role to play in sodium channel inactivation.

Overall, the study expands our understanding of sodium channel functioning and the specific effects of the mutations that lead to HPP in horses. This could potentially aid in the development of treatment options for not just equine HPP but also similar conditions in other species.

Cite This Article

APA
Hanna WJ, Tsushima RG, Sah R, McCutcheon LJ, Marban E, Backx PH. (1996). The equine periodic paralysis Na+ channel mutation alters molecular transitions between the open and inactivated states. J Physiol, 497 ( Pt 2)(Pt 2), 349-364. https://doi.org/10.1113/jphysiol.1996.sp021773

Publication

The Journal of physiology
ISSN: 0022-3751
NlmUniqueID: 0266262
Country: England
Language: English
Volume: 497 ( Pt 2)
Issue: Pt 2
Pages: 349-364

Researcher Affiliations

Hanna, W J
  • Department of Physics, University of Guelph, Ontario, Canada.
Tsushima, R G
    Sah, R
      McCutcheon, L J
        Marban, E
          Backx, P H

            MeSH Terms

            • Animals
            • Electrophysiology
            • Female
            • Horse Diseases / genetics
            • Horses
            • Ion Channel Gating / genetics
            • Membrane Potentials / physiology
            • Muscle, Skeletal / chemistry
            • Muscle, Skeletal / physiopathology
            • Mutagenesis, Site-Directed / physiology
            • Mutation / physiology
            • Oocytes / physiology
            • Paralyses, Familial Periodic / genetics
            • Phenotype
            • Rats
            • Sodium Channels / genetics
            • Sodium Channels / metabolism
            • Transfection
            • Xenopus laevis

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            Citations

            This article has been cited 2 times.
            1. Jurkat-Rott K, Lehmann-Horn F. Genotype-phenotype correlation and therapeutic rationale in hyperkalemic periodic paralysis. Neurotherapeutics 2007 Apr;4(2):216-24.
              doi: 10.1016/j.nurt.2007.02.001pubmed: 17395131google scholar: lookup
            2. D'Avanzo N, Cho HC, Tolokh I, Pekhletski R, Tolokh I, Gray C, Goldman S, Backx PH. Conduction through the inward rectifier potassium channel, Kir2.1, is increased by negatively charged extracellular residues. J Gen Physiol 2005 May;125(5):493-503.
              doi: 10.1085/jgp.200409175pubmed: 15824191google scholar: lookup
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