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ARTICLES: E. Matthews, R. Labrum, M. G. Sweeney, R. Sud, A. Haworth, P. F. Chinnery, G. Meola, S. Schorge, D. M. Kullmann, M. B. Davis, and M. G. Hanna Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis Neurology 2009; 72: 1544-1547 [Abstract] [Full text] [PDF]

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Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis

Robert L. Ruff, None   (22 July 2009)

Reply from the authors

Stephanie Schorge, Emma Matthews, Dimitri M. Kullmann and Michael G. Hanna   (22 July 2009)

Reply from the Editorialist

Stephen C. Cannon   (22 July 2009)

Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis 22 July 2009
Robert L. Ruff, Cleveland VAMC/Case Western Reserve Univ. Neurology 127(W), CVAMC, 10701 East Blvd., Cleveland, OH 44106, None Send Correspondence to journal: Re: Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis Robertlruff{at}aol.com Robert L. Ruff, et al.	Matthews et al. highlight the importance of mutations in the arginine residues in S4 voltage sensors of skeletal muscle Ca2+ and Na+ channels in the genesis of hypokalemic periodic paralysis (HypoKPP) types 1 and 2. [1] Previous studies have demonstrated that loss of charged arginine residues produces a leak current pathway through portions of the ion channel that support voltage-induced movements of the S4 segments. [2] Current flowing through the alternative ion pathway created by the S4 mutations could account for the anomalous cation depolarizing current that occurs in type 1 HypoKPP and is likely present in type 2 HypoKPP. Current passage via an alternative pathway would also explain why the anomalous depoplarizing current is not blocked by traditional Na+ or Ca2+ channel blockers. [3] The highly selective association of the arginine gating pore mutations with the HypoKPP phenotype suggests that this type of mutation is likely key to the genesis of this phenotype. The authors also consider whether other ion channel alterations associated with HypoKPP are important for creation of the phenotype. [1] Type 1 HypoKPP is associated with reduction in the outward current component of the inward rectifier K+ channel (Kir). [3] While reduced Kir may be an epiphenomena, a role for reduced Kir in the HypoKPP phenotype has been suggested. Reduced Kir is the ion channel defect responsible for Andersen syndrome, which includes a periodic paralysis phenotype. Increasing K+ current may be the mechanism of action of acetazolamide-induced improvement in HypoKPP symptoms. [4] In type 2 HypoKPP, the Na+ channel mutations reduce the available Na+ current through enhanced channel inactivation. [5] The density of Na+ may be reduced in type 1 HypoKPP. [6] Lower Na+ current density is consistent with reduced action potential conduction velocity and could contribute to the HypoKPP phenotype by reducing membrane excitability thereby facilitating paralysis due to membrane inexcitabiity. These arguments suggest the reduced Kir and Na+ currents contribute to the HypoKPP phenotype, yet they do not prove that they are critical. The arginine mutations directly produce the anomalous depolarizing current. How do the mutations reduce other currents? Perhaps the mutations, by creating an alternative path for cations to enter, may indirectly contribute to the changes in Na+ and Kir channel function by altering the intracellular ionic composition. [6] References 1. Matthews E, Labrum R, Sweeney MG, et al. Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis. Neurology 2009;72:1544-1547. 2. Struyk AF, Cannon SC. A Na+ channel mutation linked to hypokalemic periodic paralysis exposes a proton selective gating pore. J Gen Physiol 2007;130:11-20. 3. Ruff RL. Insulin Acts in Hypokalemic Periodic Paralysis by Reducing Inward Rectifier K+ Current. Neurology 1999;53:1556-1563. 4. Tricarico D, Barbieri M, Camerino DC. Acetazolamide opens the muscular KCa2+ channel: a novel mechanism of action that may explain the therapeutic effect of the drug in hypokalemic periodic paralysis. Ann Neurol 2000;48:304-312. 5. Kuzmenkin A, Muncan V, Jurkat-Rott K, et al. Enhanced inactivation and pH sensitivity of Na+ channel mutations causing hypokalemic periodic paralysis type II. Brain 2002;125:835-843. 6. Ruff RL. Skeletal muscle sodium current is reduced in hypokalemic periodic paralysis. Proc Natl Acad Sci (US) 2000;97:9832-9833. Disclosures: Dr. Ruff was the Principal Investigator of Department of Veterans Affairs Merit Reviewed Research Program, “Human Skeletal Muscle Sodium Channels and Hypokalemic Periodic Paralysis.”
Reply from the authors 22 July 2009
Stephanie Schorge, Institute of Neurology Queen Square, London, WC1N 3BG, United Kingdom, Emma Matthews, Dimitri M. Kullmann and Michael G. Hanna Send Correspondence to journal: Re: Reply from the authors s.schorge{at}ion.ucl.ac.uk Stephanie Schorge, et al.	We agree with Dr. Ruff that the functional gap still remains between the loss of S4 arginines in SCN4A and CACNA1S and the development of periodic paralysis. Specifically, the mutant S4 segments (or gating pores) indirectly impact other conductances (KIR and Na) and may alter intracellular ionic concentrations in the muscle fibers. Ruff reports that biopsied muscle fibers from HypoKPP patients depolarize (paradoxically) in low Kout and in response to insulin. [2] In a separate study, the main conductance change identified in patient cells carrying a CACNA1S S4 mutation compared to controls was a loss of sarcolemmal KATP and not a change in Ca currents. [7] Interestingly, a recent study proposed that S4-mediated cation leaks can lead to a paradoxical K-dependent membrane depolarization, which may explain the depolarizing response to a decrease in external potassium and the potassium dependence of attacks of paralysis.[8] However, the mechanism linking mutations in S4 segments of SCN4A or CACNA1S to altered KATP and insulin response is still unclear. The genetic evidence indicates that dysfunction of the S4 segment is directly linked to the pathogenesis of HypoKPP. However, a significant minority of our cohort (10%) does not have S4 mutations, which suggests that the full genetic basis of HypoKPP is still unknown. [1] Finding a clear genetic association in the remaining patients may explain the functional mechanism of HypoKPP, including how changes in CACNA1S and SCN4A S4 arginines can lead to altered sarcolemmal K conductances and altered insulin responses. References 7. Tricarico D, Servidei S, Tonali P, et al. Impairment of skeletal muscle adenosine triphosphate–sensitive K+ channels in patients with hypokalemic periodic paralysis. J Clin Invest 1999;103:675–682. 8. Jurkat-Rott K, Weber MA, Fauler M, et al. K+-dependent paradoxical membrane depolarization and Na+ overload, major and reversible contributors to weakness by ion channel leaks. Proc Natl Acad Sci USA. 2009 Mar 10;106:4036-4041. Disclosure: Dr. Schorge holds a charitable fellowship sponsored by the Worshipful Company of Pewterers; has two patents unrelated to this work; and is funded by a grant from the MRC (G0601440). Dr. Kullmann serves as an Editorial Board member of Brain, Neuron, The Journal of Neuroscience, and The Neuroscientist; and has received honoraria from GlaxoSmithKline.
Reply from the Editorialist 22 July 2009
Stephen C. Cannon, Dept of Neurology 5323 Harry Hines Blvd., UT Southwestern Medical Center, Dallas, TX 75390 Send Correspondence to journal: Re: Reply from the Editorialist steve.cannon{at}utsouthwestern.edu Stephen C. Cannon	I thank Dr. Ruff for his comments. While the enhanced Na+ channel inactivation for HypoPP Type 2 mutations may contribute to the reduced Na+ current, and therefore a more sluggish rising phase of the action potential, the fact that this effect was not reversed by artificial hyperpolarization argues that another factor must be at work. [9] Using Na+ MR spectroscopy, Jurkott-Rott et al. have recently shown an elevation of myoplasmic Na content interictally for HypoPP patients with Na or Ca channel mutations. [8] Moreover, the Na overload was exacerbated by limb cooling to induce weakness. The reduced Na+ gradient in this situation is predicted to shift the Nernst potential by 15 mV, which in turn would decrease the Na+ current by about 20% over the voltage range from -30 to -10 mV. For the Kir conductance, the ictal shift of K+ from the interstitial space to the myoplasm would increase the gradient and therefore at first glance would increase the K+ current that maintains Vrest. However, this effect is overwhelmed by the hyperpolarized shift of the rectification point for the Kir conductance in low external K+, with the end result being a marked decrease in the “outward limb” of the Kir current at the normal value of Vrest. This effective decrease in the outward Kir current and the presence of a small gating pore leak both contribute to the pathological depolarization of Vrest during an attack of HypoPP. [10] References 9. Jurkat-Rott K, Mitrovic N, Hang C, et al. Voltage-sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current. Proc Natl Acad Sci (US) 2000;97:9549-9554. 10. Struyk AF, Cannon SC. Paradoxical depolarization of Ba2+- treated muscle exposed to low extracellular K+: insights into resting potential abnormalities in hypokalemic paralysis. Muscle Nerve 2008;37:326-337. Disclosure: Dr. Cannon serves on the Scientific Advisory Committee for the Muscular Dystrophy Association.