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Sodium channel inactivation is impaired in equine hyperkalemic periodic paralysis.
Abstract: 1. Equine hyperkalemic periodic paralysis (E-HPP) is a dominantly inherited disorder of muscle that causes recurrent episodes of stiffness (myotonia) and weakness in association with elevated serum K+. Affected horses carry a mutant allele of the skeletal muscle isoform of the Na channel alpha-subunit. To understand how this mutation may cause the disease phenotype, the functional defect in Na channel behavior was defined physiologically by recording unitary currents from cell-attached patches on normal and affected equine myotubes. 2. The presence of the mutation was confirmed in our cell line by restriction digest of polymerase chain reaction (PCR)-amplified genomic DNA. Myotubes from the affected horse were heterozygous for the point mutation that codes for a Phe to Leu substitution in S3 of domain IV. This assay provides a rapid technique to screen for the mutation in horses at risk. 3. The primary physiological defect in mutant Na channels was an impairment of inactivation. This defect was manifest as bursts of persistent activity during which the channel closed and reopened throughout a maintained depolarization. Disrupted inactivation slowed the decay of the ensemble-averaged current and produced an eightfold increase in the steady-state open probability measured at the end of a 40-ms pulse. This point mutation identifies a new region of the alpha subunit that is important for rapid inactivation of the channel. 4. The persistent Na current was produced by a distinct mode of gating. Failure of a mutant channel to inactivate was infrequent and occurred in groups of consecutive trials.(ABSTRACT TRUNCATED AT 250 WORDS)
Publication Date: 1995-05-01 PubMed ID: 7623088DOI: 10.1152/jn.1995.73.5.1892Google Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
- Research Support
- Non-U.S. Gov't
- Research Support
- U.S. Gov't
- P.H.S.
Summary
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This research article discusses a study on equine hyperkalemic periodic paralysis (E-HPP), a genetic muscle disorder in horses leading to stiffness and weaknesses correlated with high serum potassium levels. The study uses a microscopic approach to explore how a particular mutation in the skeletal muscle sodium channel can cause this disorder, focusing on its effects on the closing and reopening of the channel.
Research Approach and Methodology
- The researchers sought to clarify how a specific mutation could be linked to E-HPP by analyzing the functional behavior of sodium channels in horse myotubes. To do so, they performed physiological tests, recording unitary currents from cell-attached patches on normal and affected equine myotubes.
- They employed restriction digestion of polymerase chain reaction (PCR)-amplified genomic DNA to validate the presence of the mutation in the affected cells under examination. This specific mutation changed the phenylalanine (Phe) to leucine (Leu) in the S3 domain of the sodium channel’s alpha subunit. The described assessment offers a quick way to check for this mutation in horses that might be at risk for E-HPP.
Findings
- The researchers found that this mutation primarily interferes with the inactivation (closing) of the mutant sodium channels. Instead of closing as normal during maintained depolarization, the channels were characterized by bursts of persistent activity, during which the channel closed and reopened.
- The impaired inactivation disrupted the decay of ensemble-averaged current and resulted in an eightfold rise in the steady-state opening probability, measured at the end of a 40-ms pulse. This shows that this particular point mutation affects a region of the alpha subunit that is crucial for rapid inactivation of the channel.
- The researchers also found that the extended sodium current was generated by a specific way of gating. The failure of a mutant channel to inactivate was not frequent and typically occurred in clusters of successive trials.
Conclusions
- This research provides a physiological understanding of how a specific mutation can cause equine hyperkalemic periodic paralysis. By examining the sodium channels’ behavior in horse muscle cells, they identified the primary dysfunction being the impaired inactivation, leading to bursts of persistent activity and an abnormal decay of ensemble-averaged current.
- These findings can function as an entry point for further studies, as well as potential development of diagnostic and treatment approaches for this genetic disorder in horses.
Cite This Article
APA
Cannon SC, Hayward LJ, Beech J, Brown RH.
(1995).
Sodium channel inactivation is impaired in equine hyperkalemic periodic paralysis.
J Neurophysiol, 73(5), 1892-1899.
https://doi.org/10.1152/jn.1995.73.5.1892 Publication
Researcher Affiliations
- Department of Neurobiology, Harvard Medical School, Boston 02115, USA.
MeSH Terms
- Animals
- Electrophysiology
- Horse Diseases / genetics
- Horses
- Models, Genetic
- Muscle, Skeletal / physiology
- Paralyses, Familial Periodic / genetics
- Paralyses, Familial Periodic / veterinary
- Phenotype
- Point Mutation
- Polymerase Chain Reaction
- Sodium Channels / genetics
- Sodium Channels / physiology
- Time Factors
Grant Funding
- AR-41025 / NIAMS NIH HHS
- AR-42703 / NIAMS NIH HHS
Citations
This article has been cited 16 times.- Mantegazza M, Cestèle S, Catterall WA. Sodium channelopathies of skeletal muscle and brain. Physiol Rev 2021 Oct 1;101(4):1633-1689.
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