Leaky sodium channels from voltage sensor mutations in periodic paralysis, but not paramyotonia

Francis, David G.; Rybalchenko, Volodymyr; Struyk, Arie; Cannon, Stephen C.

doi:10.1212/wnl.0b013e318219fb57

Cited by 50 publications

(66 citation statements)

References 25 publications

(37 reference statements)

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“…The remarkable clustering of HypoPP mutations at arginine residues in the S4 voltage sensors of Na V 1.4 or Ca V 1.1 implicate a common mechanism wherein these S4 mutations create a voltage-dependent leak or gating pore current (16,17). Indeed, gating pore currents have been demonstrated for all 6 Na V 1.4 HypoPP mutations tested in oocytes (21) and in muscle fibers from our knockin Na V 1.4 R669H HypoPP mouse (22). The poor expression of Ca V 1.1 in heterologous systems has precluded the ability to test whether Ca V 1.1 HypoPP mutant channels support anomalous gating pore currents.…”

Section: Figurementioning

confidence: 94%

“…The sensitivity for detecting gating pore currents was further increased by subtracting the remaining nonspecific currents after the addition of 3.5 mM La 3+ , which is known to block gating pore currents in mutant Na V 1.4 channels (17,21). In comparison with WT fibers, the La 3+ -sensitive currents recorded from R528H m/m fibers had a larger inward component (i.e., negative amplitude) at all test potentials below -55 mV (P < 0.05; Figure 6A).…”

Section: Figurementioning

confidence: 99%

“…Missense mutations of the S4 segment may produce a leak or gating pore current that allows ions to pass through this aberrant conduction pathway (18,19). In frog oocytes, where high levels of membrane expression for Na V 1.4 can be achieved, small gating pore currents have been detected for all 6 Na V 1.4 HypoPP mutations studied to date (16,17,20,21). We also detected a gating pore current in voltage-clamped muscle fibers from a mouse model of HypoPP with a knock-in Na V 1.4 R669H mutation (22).…”

Section: Introductionmentioning

confidence: 99%

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A calcium channel mutant mouse model of hypokalemic periodic paralysis

Hernández‐Ochoa

et al. 2012

J. Clin. Invest.

135

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Hypokalemic periodic paralysis (HypoPP) is a familial skeletal muscle disorder that presents with recurrent episodes of severe weakness lasting hours to days associated with reduced serum potassium (K + ). HypoPP is genetically heterogeneous, with missense mutations of a calcium channel (Ca V 1.1) or a sodium channel (Na V 1.4) accounting for 60% and 20% of cases, respectively. The mechanistic link between Ca V 1.1 mutations and the ictal loss of muscle excitability during an attack of weakness in HypoPP is unknown. To address this question, we developed a mouse model for HypoPP with a targeted Ca V 1.1 R528H mutation. The Ca v 1.1 R528H mice had a HypoPP phenotype for which low K + challenge produced a paradoxical depolarization of the resting potential, loss of muscle excitability, and weakness. A vacuolar myopathy with dilated transverse tubules and disruption of the triad junctions impaired Ca 2+ release and likely contributed to the mild permanent weakness. Fibers from the Ca V 1.1 R528H mouse had a small anomalous inward current at the resting potential, similar to our observations in the Na V 1.4 R669H HypoPP mouse model. This "gating pore current" may be a common mechanism for paradoxical depolarization and susceptibility to HypoPP arising from missense mutations in the S4 voltage sensor of either calcium or sodium channels.

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Section: Figurementioning

confidence: 94%

Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A calcium channel mutant mouse model of hypokalemic periodic paralysis

Hernández‐Ochoa

et al. 2012

J. Clin. Invest.

135

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“…Blockers were used to suppress Na + , K + , and Ca 2+ currents, and a chloride-free extracellular solution was used to suppress the Cl -current. The residual current was still large (~5 nA/nF at -100 mV) compared with the predicted amplitude of the gating pore current (~1 nA/nF), and so the sensitivity for detection was further increased by extracting the component of current blocked by 3.5 mM lanthanum, which produces approximately 65% block of the gating pore current (24). Fibers from R669H m/m mice showed an increased inward current at test potentials more negative than -20 mV compared with those from WT mice ( Figure 5D).…”

Section: Figurementioning

confidence: 99%

A sodium channel knockin mutant (NaV1.4-R669H) mouse model of hypokalemic periodic paralysis

Burns³

et al. 2011

J. Clin. Invest.

109

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Hypokalemic periodic paralysis (HypoPP) is an ion channelopathy of skeletal muscle characterized by attacks of muscle weakness associated with low serum K + . HypoPP results from a transient failure of muscle fiber excitability. Mutations in the genes encoding a calcium channel (Ca V 1.1) and a sodium channel (Na V 1.4) have been identified in HypoPP families. Mutations of Na V 1.4 give rise to a heterogeneous group of muscle disorders, with gain-of-function defects causing myotonia or hyperkalemic periodic paralysis. To address the question of specificity for the allele encoding the Na V 1.4-R669H variant as a cause of HypoPP and to produce a model system in which to characterize functional defects of the mutant channel and susceptibility to paralysis, we generated knockin mice carrying the ortholog of the gene encoding the Na V 1.4-R669H variant (referred to herein as R669H mice). Homozygous R669H mice had a robust HypoPP phenotype, with transient loss of muscle excitability and weakness in low-K + challenge, insensitivity to high-K + challenge, dominant inheritance, and absence of myotonia. Recovery was sensitive to the Na + /K + -ATPase pump inhibitor ouabain. Affected fibers had an anomalous inward current at hyperpolarized potentials, consistent with the proposal that a leaky gating pore in R669H channels triggers attacks, whereas a reduction in the amplitude of action potentials implies additional loss-of-function changes for the mutant Na V 1.4 channels.

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“…1,2 In sodium channels, charge-reducing mutations of the outer S4 arginines R1 or R2 in domains I to III produce an inwardly rectifying proton or cation current observed with hyperpolarization of membrane potential as experienced with a drop in serum potassium. [3][4][5][6] Present models of hypokalemic periodic paralysis incorporate this leak or "omega" current as a contributing factor in the pathogenesis of the disorder (for a review see refs). 6,7 Voltage sensor mutations at R3 that produce a depolarization-activated omega current were first identified for normokalemic periodic paralysis mutations in domain II of the sodium channel Na V 1.4 8 and domain IV of the calcium channel Ca V 1.1.…”

Section: Introductionmentioning

confidence: 99%

Domain III S4 in closed-state fast inactivation: Insights from a periodic paralysis mutation

Groome

Jurkat‐Rott²,

Lehmann‐Horn³

2014

Channels

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Leaky sodium channels from voltage sensor mutations in periodic paralysis, but not paramyotonia

Abstract: Background: Hypokalemic periodic paralysis (HypoPP) is associated with mutations in either the

Cited by 50 publications

References 25 publications

A calcium channel mutant mouse model of hypokalemic periodic paralysis

A calcium channel mutant mouse model of hypokalemic periodic paralysis

A sodium channel knockin mutant (NaV1.4-R669H) mouse model of hypokalemic periodic paralysis

Domain III S4 in closed-state fast inactivation: Insights from a periodic paralysis mutation

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