Defective slow inactivation of sodium channels contributes to familial periodic paralysis

Ruff, Robert L.; Cannon, Stephen C.

doi:10.1212/wnl.54.11.2191

Cited by 83 publications

(5 citation statements)

References 5 publications

(9 reference statements)

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“…Sodium channel HypoPP mutations are located primarily on the S4 voltage sensors of domains II and III where they neutralize positively charged residues hindering proper voltage sensor function (Kontis et al, 1997; Kuhn and Greeff, 1999; Matthews et al, 2009; Ruff, 2010). HypoPP Na v 1.4 mutations (unlike other Na v 1.4 mutations which cause a gain-of-function by enhancing activation or impairing inactivation) cause a channel loss of function by enhancing channel inactivation which, can be achieved by enhancing fast inactivation, slow inactivation or both reducing the availability of these sodium channels (Jurkat-Rott et al, 2000; Ruff and Cannon, 2000; Struyk et al, 2000; Bendahhou et al, 2001; Kuzmenkin et al, 2002). At normal muscle resting membrane potentials (RMP), about 70% of the Na v 1.4 channels are available for activation which is enough to generate an AP.…”

Section: Skeletal Muscle Pathophysiologymentioning

confidence: 99%

Skeletal muscle Na+ channel disorders

Simkin¹

2011

Front. Pharmacol.

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Five inherited human disorders affecting skeletal muscle contraction have been traced to mutations in the gene encoding the voltage-gated sodium channel Nav1.4. The main symptoms of these disorders are myotonia or periodic paralysis caused by changes in skeletal muscle fiber excitability. Symptoms of these disorders vary from mild or latent disease to incapacitating or even death in severe cases. As new human sodium channel mutations corresponding to disease states become discovered, the importance of understanding the role of the sodium channel in skeletal muscle function and disease state grows.

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Section: Skeletal Muscle Pathophysiologymentioning

confidence: 99%

Skeletal muscle Na+ channel disorders

Simkin¹

2011

Front. Pharmacol.

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“…Intact slow inactivation should terminate the influx of sodium ions into muscle fibers through channels with defective fast inactivation within several minutes. 27 Several studies 28,29 showed that some but not all hyperkalemic PP-causing mutations reduce slow sodium channel inactivation and should thereby increase the permanent sodium influx into the muscle fibers, presumably generating long-lasting depolarization. In contrast, PC-causing mutations destabilize fast inactivation while slow channel inactivation is not affected.…”

Section: Hyperkalemic Pp: Is the Incomplete Slow Inactivation Importamentioning

confidence: 99%

Genotype-Phenotype Correlation and Therapeutic Rationale in Hyperkalemic Periodic Paralysis

Jurkat‐Rott¹,

Lehmann‐Horn²

2007

Neurotherapeutics

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Summary:Familial hyperkalemic periodic paralysis (PP) is a dominantly inherited muscle disease characterized by attacks of flaccid weakness and intermittent myotonia. Some patients experience muscle stiffness that is aggravated by cold and exercise, bordering on the diagnosis of paramyotonia congenita. Hyperkalemic PP and paramyotonia congenita are allelic diseases caused by gain-of-function mutations of the skeletal muscle sodium channel, Nav1.4, which is essential for the generation of skeletal muscle action potentials. In this review, the functional and clinical consequences of the mutations and therapeutic strategies are reported and the differential diagnoses discussed. Also, the question is addressed of whether hyperkalemic PP is truly a different entity than normokalemic PP. Additionally, the differential diagnosis of Andersen-Tawil syndrome in which hyperkalemic PP attacks may occur will be briefly introduced. Last, because hyperkalemic PP has been described to be associated with an R83H mutation of a MiRP2 potassium channel subunit, evidence refuting disease-causality in this case will be discussed.

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“…Slow inactivation increases the action potential threshold, limits the duration of bursts of action potentials, limits propagation of action potentials into dendritic regions, and is implicated in adaptation of pacemaking neurons to varying inputs (Colbert et al, 1997;Jung et al, 1997;Mickus et al, 1999;Carr et al, 2002;Do and Bean, 2003). Mutations that impair slow inactivation cause periodic paralysis of skeletal muscle and arrhythmias in heart (Ruff and Cannon, 2000;Wang et al, 2000), and many point mutations in different regions of sodium channels have small but significant effects on slow inactivation (Balser et al, 1996;Cummins and Sigworth, 1996;Kontis and Goldin, 1997;Mitrovic et al, 2000;Nau et al, 1999;O'Reilly et al, 2001;Ong et al, 2000;Todt et al, 1999;Vilin et al, 1999Vilin et al, , 2001Wang and Wang, 1997;Xiong et al, 2003). However, in spite of this extensive research, the molecular mechanism of slow inactivation is unknown, and no point mutations have been described that substantially block slow inactivation and thereby define its essential molecular determinants.…”

Section: Introductionmentioning

confidence: 99%

Neuromodulation of Na+ Channel Slow Inactivation via cAMP-Dependent Protein Kinase and Protein Kinase C

Chen

Surmeier

et al. 2006

Neuron

133

114

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Neurotransmitters modulate sodium channel availability through activation of G protein-coupled receptors, cAMP-dependent protein kinase (PKA), and protein kinase C (PKC). Voltage-dependent slow inactivation also controls sodium channel availability, synaptic integration, and neuronal firing. Here we show by analysis of sodium channel mutants that neuromodulation via PKA and PKC enhances intrinsic slow inactivation of sodium channels, making them unavailable for activation. Mutations in the S6 segment in domain III (N1466A,D) either enhance or block slow inactivation, implicating S6 segments in the molecular pathway for slow inactivation. Modulation of N1466A channels by PKC or PKA is increased, whereas modulation of N1466D is nearly completely blocked. These results demonstrate that neuromodulation by PKA and PKC is caused by their enhancement of intrinsic slow inactivation gating. Modulation of slow inactivation by neurotransmitters acting through G protein-coupled receptors, PKA, and PKC is a flexible mechanism of cellular plasticity controlling the firing behavior of central neurons.

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Defective slow inactivation of sodium channels contributes to familial periodic paralysis

Cited by 83 publications

References 5 publications

Skeletal muscle Na+ channel disorders

Skeletal muscle Na+ channel disorders

Genotype-Phenotype Correlation and Therapeutic Rationale in Hyperkalemic Periodic Paralysis

Neuromodulation of Na+ Channel Slow Inactivation via cAMP-Dependent Protein Kinase and Protein Kinase C

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