Sodium channel inactivation is impaired in equine hyperkalemic periodic paralysis

Author:

Cannon S. C.1,Hayward L. J.1,Beech J.1,Brown R. H.1

Affiliation:

1. Department of Neurobiology, Harvard Medical School, Boston 02115,USA.

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)

Publisher

American Physiological Society

Subject

Physiology,General Neuroscience

Cited by 45 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Muscle Disorders of Equine Athletes;Equine Sports Medicine and Surgery;2024

2. Sodium channelopathies of skeletal muscle and brain;Physiological Reviews;2021-10-01

3. Genetics of Equine Muscle Disease;Veterinary Clinics of North America: Equine Practice;2020-08

4. Diseases of Muscle;Large Animal Internal Medicine;2020

5. Ancient genomes revisit the ancestry of domestic and Przewalski’s horses;Science;2018-04-06

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