Loss of Na+ channel inactivation by anemone toxin (ATX II) mimics the myotonic state in hyperkalaemic periodic paralysis

S. C. Cannon, D. P. Corey

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Abstract

1. Mutations that impair inactivation of the sodium channel in skeletal muscle have recently been postulated to cause several heritable forms of myotonia in man. A peptide toxin from Anemonia sulcata (ATX II) selectively disrupts the inactivation mechanism of sodium channels in a way that mimics these mutations. We applied ATX II to rat skeletal muscle to test the hypothesis that myotonia is inducible by altered sodium channel function. 2. Single-channel sodium currents were measured in blebs of surface membrane that arose from the mechanically disrupted fibres. ATX II impaired inactivation as demonstrated by persistent reopenings of sodium channels at strongly depolarized test potentials. A channel failed to inactivate, however, in only a small proportion of the depolarizing steps. With micromolar amounts of ATX II, the ensemble average open probability at the steady state was 0.01-0.02. 3. Ten micromolar ATX II slowed the relaxation of tension after a single twitch by an order of magnitude. Delayed relaxation is the in vitro analogue of the stiffness experienced by patients with myotonia. However, peak twitch force was not affected within the range of 0-10 μM ATX II. 4. Intracellular injection of a long-duration, constant current pulse elicited a train of action potentials in ATX II-treated fibres. After-depolarizations and repetitive firing often persisted beyond the duration of the stimulus. Trains of action potentials varied spontaneously in amplitude and firing frequency in a similar way to the electromyogram of a myotonic muscle. Both the after-depolarization and the post-stimulus firing were abolished by detubulating the fibres with glycerol. 5. We conclude that a loss of sodium channel inactivation alone, without changes in resting membrane conductance, is sufficient to produce the electrical and mechanical features of myotonia. Furthermore, in support of previous studies on myotonic muscle from patients, this model provides direct evidence that only a small proportion of sodium channels needs to function abnormally to cause myotonia.

Original languageEnglish (US)
Pages (from-to)501-520
Number of pages20
JournalJournal of Physiology
Volume466
StatePublished - 1993

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Sodium Channels
Myotonia
Paralysis
Action Potentials
Skeletal Muscle
Muscles
Mutation
Membranes
Electromyography
Blister
toxin II (Anemonia sulcata)
Glycerol
Peptides
Injections

ASJC Scopus subject areas

  • Physiology

Cite this

Loss of Na+ channel inactivation by anemone toxin (ATX II) mimics the myotonic state in hyperkalaemic periodic paralysis. / Cannon, S. C.; Corey, D. P.

In: Journal of Physiology, Vol. 466, 1993, p. 501-520.

Research output: Contribution to journalArticle

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N2 - 1. Mutations that impair inactivation of the sodium channel in skeletal muscle have recently been postulated to cause several heritable forms of myotonia in man. A peptide toxin from Anemonia sulcata (ATX II) selectively disrupts the inactivation mechanism of sodium channels in a way that mimics these mutations. We applied ATX II to rat skeletal muscle to test the hypothesis that myotonia is inducible by altered sodium channel function. 2. Single-channel sodium currents were measured in blebs of surface membrane that arose from the mechanically disrupted fibres. ATX II impaired inactivation as demonstrated by persistent reopenings of sodium channels at strongly depolarized test potentials. A channel failed to inactivate, however, in only a small proportion of the depolarizing steps. With micromolar amounts of ATX II, the ensemble average open probability at the steady state was 0.01-0.02. 3. Ten micromolar ATX II slowed the relaxation of tension after a single twitch by an order of magnitude. Delayed relaxation is the in vitro analogue of the stiffness experienced by patients with myotonia. However, peak twitch force was not affected within the range of 0-10 μM ATX II. 4. Intracellular injection of a long-duration, constant current pulse elicited a train of action potentials in ATX II-treated fibres. After-depolarizations and repetitive firing often persisted beyond the duration of the stimulus. Trains of action potentials varied spontaneously in amplitude and firing frequency in a similar way to the electromyogram of a myotonic muscle. Both the after-depolarization and the post-stimulus firing were abolished by detubulating the fibres with glycerol. 5. We conclude that a loss of sodium channel inactivation alone, without changes in resting membrane conductance, is sufficient to produce the electrical and mechanical features of myotonia. Furthermore, in support of previous studies on myotonic muscle from patients, this model provides direct evidence that only a small proportion of sodium channels needs to function abnormally to cause myotonia.

AB - 1. Mutations that impair inactivation of the sodium channel in skeletal muscle have recently been postulated to cause several heritable forms of myotonia in man. A peptide toxin from Anemonia sulcata (ATX II) selectively disrupts the inactivation mechanism of sodium channels in a way that mimics these mutations. We applied ATX II to rat skeletal muscle to test the hypothesis that myotonia is inducible by altered sodium channel function. 2. Single-channel sodium currents were measured in blebs of surface membrane that arose from the mechanically disrupted fibres. ATX II impaired inactivation as demonstrated by persistent reopenings of sodium channels at strongly depolarized test potentials. A channel failed to inactivate, however, in only a small proportion of the depolarizing steps. With micromolar amounts of ATX II, the ensemble average open probability at the steady state was 0.01-0.02. 3. Ten micromolar ATX II slowed the relaxation of tension after a single twitch by an order of magnitude. Delayed relaxation is the in vitro analogue of the stiffness experienced by patients with myotonia. However, peak twitch force was not affected within the range of 0-10 μM ATX II. 4. Intracellular injection of a long-duration, constant current pulse elicited a train of action potentials in ATX II-treated fibres. After-depolarizations and repetitive firing often persisted beyond the duration of the stimulus. Trains of action potentials varied spontaneously in amplitude and firing frequency in a similar way to the electromyogram of a myotonic muscle. Both the after-depolarization and the post-stimulus firing were abolished by detubulating the fibres with glycerol. 5. We conclude that a loss of sodium channel inactivation alone, without changes in resting membrane conductance, is sufficient to produce the electrical and mechanical features of myotonia. Furthermore, in support of previous studies on myotonic muscle from patients, this model provides direct evidence that only a small proportion of sodium channels needs to function abnormally to cause myotonia.

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