Enhanced inactivation and pH sensitivity of Na+ channel mutations causing hypokalaemic periodic paralysis type II

Kuzmenkin, Alexey; Muncan, Vanesa; Jurkat‐Rott, Karin; Hang, Chao; Lerche, Holger; Lehmann‐Horn, Frank; Mitrović, Nenad

doi:10.1093/brain/awf071

Cited by 72 publications

(53 citation statements)

References 32 publications

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“…55 Here, the mechanism might also involve regulation of potassium ion and proton concentrations. To determine whether a change of the proton concentration influences the gating of SCN4A mutants, Kuzmenkin et al 59 used pH values ranging from 6.4 to 8.4 in bath or pipette solutions. The change of extracellular pH had profound effects on steady-state activation and inactivation of the wild-type channels, probably due to the change in surface potential but also to a direct blockade of the sodium channels.…”

Section: Acetazolamidementioning

confidence: 99%

Episodic Ataxia Type 2

Strupp¹,

Zwergal²,

Brandt³

2007

Neurotherapeutics

162

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Summary: Episodic ataxia type 2 (EA 2) is a rare neurological disorder of autosomal dominant inheritance resulting from dysfunction of a voltage-gated calcium channel. It manifests with recurrent disabling attacks of imbalance, vertigo, and ataxia, and can be provoked by physical exertion or emotional stress. In the spell-free interval, patients present with central ocular motor dysfunction, mainly downbeat nystagmus. A slow progression of cerebellar signs accompanied by a slight atrophy of midline cerebellar structures is commonly observed during the course of the disease. EA 2 is caused most often by the loss of function mutations of the calcium channel gene CACNA1A, which encodes the Ca V 2.1 subunit of the P/Q-type calcium channel and is primarily expressed in Purkinje cells. To date, more than 30 mutations have been described. Two effective treatment options have been established for EA 2: acetazolamide (ACTZ), which probably changes the intracellular pH and thereby the transmembraneous potential, and 4-aminopyridine (4-AP), a potassium channel blocker. Approximately 70% of all patients respond to treatment with ACTZ, but the effect is often only transient. In an open trial, 4-AP prevented attacks in five of six patients with EA 2, most likely by increasing the resting activity and excitability of the Purkinje cells. These findings were confirmed by experiments in animal models of EA 2. Many aspects of the pathophysiology (e.g., induction of the attacks) and treatment of EA 2 (e.g., mode of action of ACTZ and 4-AP) still remain unclear and need to be addressed in further animal and clinical studies.

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Section: Acetazolamidementioning

confidence: 99%

Episodic Ataxia Type 2

Strupp¹,

Zwergal²,

Brandt³

2007

Neurotherapeutics

162

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“…The convergence of these mutations on the outermost two gating charges of voltage sensors in two different proteins strongly implicates voltage sensor dysfunction in this disease. Standard electrophysiological studies of these mutant sodium channels expressed in heterologous cells revealed only mildly enhanced fast and/or slow inactivation (9)(10)(11)(12), but more sensitive recordings in the cutopen oocyte preparation showed that HypoPP mutant Na V 1.4 channels conduct gating pore currents caused by movement of protons and cations through the mutant voltage sensor (13,14). Gating pore current constitutes a gain-of-function effect because steady influx of cations at resting membrane potential would cause depolarization and sodium overload that impair action potential generation.…”

mentioning

confidence: 99%

Depolarization-activated gating pore current conducted by mutant sodium channels in potassium-sensitive normokalemic periodic paralysis

Sokolov

Scheuer

Catterall

2008

Proc. Natl. Acad. Sci. U.S.A.

125

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Some inherited periodic paralyses are caused by mutations in skeletal muscle Na V1.4 sodium channels that alter channel gating and impair action potential generation. In the case of hypokalemic periodic paralysis, mutations of one of the outermost two gating charges in the S4 voltage sensor in domain II of the Na V1.4 ␣ subunit induce gating pore current, resulting in a leak of sodium or protons through the voltage sensor that causes depolarization, sodium overload, and contractile failure correlated with low serum potassium. Potassium-sensitive normokalemic periodic paralysis (NormoPP) is caused by mutations in the third gating charge in domain II of the Na V1.4 channel. Here, we report that these mutations in rat Na V1.4 (R669Q/G/W) cause gating pore current that is activated by depolarization and therefore is conducted in the activated state of the voltage sensor. In addition, we find that this gating pore current is retained in the slow-inactivated state and is deactivated only at hyperpolarized membrane potentials. Gating pore current through the mutant voltage sensor of slowinactivated NormoPP channels would cause increased sodium influx at the resting membrane potential and during trains of action potentials, depolarize muscle fibers, and lead to contractile failure and cellular pathology in NormoPP.skeletal muscle ͉ Nav 1.4 ͉ gating charge ͉ voltage sensor V oltage-gated sodium channels in skeletal muscle (Na V 1.4) generate action potentials that initiate muscle contraction in response to nerve stimulation. They are complexes of a large pore-forming ␣-subunit and a small, auxiliary ␤1-subunit (1-4). The ␣-subunits are organized in 4 repeated domains with 6 transmembrane segments (S1-S6) and a reentrant P loop between S5 and S6 (4, 5). The voltage sensitivity of sodium channels arises from the force of the transmembrane electric field exerted on arginine residues in 3-residue repeat motifs in the S4 transmembrane segments, which move outward upon depolarization and initiate a conformational change that opens the central pore (4, 6).The periodic paralyses are rare, dominantly inherited muscle disorders characterized by episodic attacks of muscle weakness (7). Hyperkalemic periodic paralysis (HyperPP) and paramyotonia congenita are caused by mutations in the ␣ subunit of skeletal muscle Na V 1.4 channels that are widely spread through the protein and usually cause a gain-of-function by impairing fast and/or slow inactivation (8). Increased sodium channel activity leads to depolarization, hyperexcitability, and either repetitive firing or depolarization block. In contrast, hypokalemic periodic paralysis (HypoPP) is caused by mutations in both the ␣-subunit of the Na V 1.4 channel and the homologous ␣1-subunit of the skeletal muscle Ca V 1.1 channel, which initiates excitationcontraction coupling (8). In HypoPP, mutations in both of these large channel proteins specifically target the outermost two gating-charge-carrying arginine residues in their S4 voltage sensors in domains II, III, or IV. The convergence...

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“…Biophysical parameters suggest a loss of function effect, an enhanced slow inactivation being most frequently observed, in contrast with sodium channel mutations causing other types of periodic paralysis where a gain-of-function was demonstrated. 42,46,[49][50][51] Accordingly, recording of muscle fibers obtained from muscle biopsies showed a reduced current density and a slower upstroke and decreased action potentials when compared with controls. 42 As for the calcium channel, these observations are insufficient to understand how sodium channel mutations could provoke muscle fiber paralysis induced by depolarization and hypokalemia.…”

Section: 44mentioning

confidence: 97%

Hypokalemic Periodic Paralysis: A Model for a Clinical and Research Approach to a Rare Disorder

et al. 2007

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Summary:Rare diseases have attracted little attention in the past from physicians and researchers. The situation has recently changed for several reasons. First, patient associations have successfully advocated their cause to institutions and governments. They were able to argue that, taken together, rare diseases affect approximately 10% of the population in developed countries. Second, almost 80% of rare diseases are of genetic origin. Advances in genetics have enabled the identification of the causative genes. Unprecedented financial support has been dedicated to research on rare diseases, as well as to the development of referral centers aimed at improving the quality of care. This expenditure of resources is justified by the experience in cystic fibrosis, which demonstrated that improved care delivered by specialized referral centers resulted in a dramatic increase of life expectancy. Moreover, clinical referral centers offer the unique possibility of developing high quality clinical research studies, not otherwise possible because of the geographic dispersion of patients. This is the case in France where national referral centers for rare diseases were created, including one for muscle channelopathies. The aim of this center is to develop appropriate care, clinical research, and teaching on periodic paralysis and myotonia. In this review, we plan to demonstrate how research has improved our knowledge of hypokalemic periodic paralysis and the way we evaluate, advise, and treat patients. We also advocate for the establishment of international collaborations, which are mandatory for the follow-up of cohorts and conduct of definitive therapeutic trials in rare diseases.

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Enhanced inactivation and pH sensitivity of Na+ channel mutations causing hypokalaemic periodic paralysis type II

Cited by 72 publications

References 32 publications

Episodic Ataxia Type 2

Episodic Ataxia Type 2

Depolarization-activated gating pore current conducted by mutant sodium channels in potassium-sensitive normokalemic periodic paralysis

Hypokalemic Periodic Paralysis: A Model for a Clinical and Research Approach to a Rare Disorder

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