ArticlePflugers Archiv : European journal of physiology2003
Impaired slow inactivation due to a polymorphism and substitutions of Ser-906 in the II-III loop of the human Nav1.4 channel.
Article in Pflugers Archiv : European journal of physiology, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 25 citations in OpenAlex.
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- Myotonic dystrophy type 2 and modifier genes: an update on clinical and pathomolecular aspects.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2017Review
- [Pharmacogenetics in anesthesia and intensive care medicine : Clinical and legal challenges exemplified by malignant hyperthermia].Der Anaesthesist · 2016Review
- Rare KCNJ18 variants do not explain hypokalaemic periodic paralysis in 263 unrelated patients.Journal of neurology, neurosurgery, and psychiatry · 2016Article
- Myotonic Dystrophy Type 2: An Update on Clinical Aspects, Genetic and Pathomolecular Mechanism.Journal of neuromuscular diseases · 2015Article
- The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill.Physiological reviews · 2015Review
- Article
- Sodium channelopathies of skeletal muscle result from gain or loss of function.Pflugers Archiv : European journal of physiology · 2010Review
- Muscle channelopathies and critical points in functional and genetic studies.The Journal of clinical investigation · 2005Review
- Rapid protein kinase C-dependent reduction of rat skeletal muscle voltage-gated sodium channels by ciliary neurotrophic factor.The Journal of physiology · 2005Article
- Novel isoforms of the sodium channels Nav1.8 and Nav1.5 are produced by a conserved mechanism in mouse and rat.The Journal of biological chemistry · 2004Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The loop connecting domains II and III of the sodium channel alpha-subunit is not known to have a major effect on channel gating. Recently mutations in the II-III loop of various sodium channel isoforms have been reported to cause channelopathies suggesting the functional importance of this region. In the II-III loop of the skeletal muscle isoform Na(v)1.4, we found a Ser-to-Thr substitution at position 906 in 5% of patients with dyskalemic periodic paralysis but also in 4% of healthy human individuals. To investigate whether this position is important for channel gating, we characterized the following amino acids at 906 by whole-cell patch-clamp experiments: Gln, Ser, Thr, Cys, Pro, Val, ordered according to their hydrophobicity. All substitutions mainly affected slow inactivation. For example, Gln caused a +13-mV right-shift of the steady-state slow inactivation curve, and entry into slow inactivation was 6 times slower compared with Ser, leading to a destabilization of the slow inactivated state; in contrast, Val, at the other end of the hydrophobicity spectrum, shifted the steady-state slow inactivation curve by -6 mV and slowed the recovery from the slow inactivated state threefold compared with Ser, resulting in an enhancement of slow inactivation. Recovery from the slow inactivated state was also slowed by Pro, Cys and Thr. Our results suggest that (1) a benign polymorphism affects channel function, (2) the II-III loop is important for slow inactivation, and (3) the effects on slow inactivation may depend on the hydrophobicity of the residue at position 906.
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