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Commentary

Skeletal muscle sodium current is reduced inhypokalemic periodic paralysisRobert L. Ruff*

Departments of Neurology and Neuroscience, Case Western Reserve University School of Medicine, Louis Stokes Cleveland Veterans Affairs Medical Center,University Hospitals of Cleveland, Cleveland, OH 44106

Hypok alemic perio dic paralysis (Hy-poPP), described a recent issue ofPNAS by Jurkat-Rott and colleagues (1),has great scientific and clinical interestbecause its pathophysiology touches onseveral important properties of skeletalmuscle. Besides providing the force formovement, skeletal muscle is an electri-cally excitable tissue and an importantendocrine target organ as the largestprotein store for humans (2). Jurkat-Rott et al. (1) defined some of the ab-normalities in surface membrane ioniccurrents that are responsible for the phe-notype of HypoPP. HypoPP is an auto-somal dominant disease characterized byepisodic attacks of muscle paralysis usu-ally associated with hypokalemia. Paral-

ysis is caused by membrane depolariza-tion triggering sodium channel inactiva-tion, which renders the membraneinexcitable (35). Membrane hyperexcit-ability, such as myotonia, is never asso-

ciated with HypoPP. Insulin administra-tion may trigger a paralytic attack with-out appreciable hypokalemia (35). Thefirst recognized linkage of HypoPP wasto chromosome 1Q3132 (68). The de-fective gene (CACNA1S) encodes a skel-etal muscle dihydropyridine-sensitive orL-type calcium channel. Two mutationshave been described in segment 4 ofdomain 2 (D2S4, Arg-5283His) andD4S4 (Arg-12393His) of the -subunitof the skeletal muscle L-type calciumchannel. A third less common mutation alsoinvolves D4S4 (Arg-12393Gly) (5, 7, 9,

10). Two recent studies demonstrated thatpoint mutations in the SCN4A gene affect-ing D2S4 of the -subunit of the matureinnervated and tetrodotoxin-sensitive iso-form of the skeletal muscle sodium channelcan produce the phenotype of HypoPP.Bulmanet al. (11) described one family withan Arg-6693His mutation. In this issue,Jurkat-Rottet al.(1) described five families,each of which had one of two mutations

Arg-6723His or Arg-6723Gly.

HypoPP Patients with Sodium or Calcium

Channel Mutations Have Similar Phenotypes.

Jurkat-Rott et al. (1) demonstrated thatHypoPP patients with sodium channel mu-tations shared the salient clinical featuresfound in patients with calcium channel mu-tations (Table 1). Subjects with sodiumchannel mutations had episodes of paralysisassociated with hypokalemia. Muscle fibers

were depolarized and inexcitable during pa-ralysis. Hypokalemia triggered depolariza-

tion, and insulin potentiated the depolariza-tion andparalysis. Studies performedbeforethe channel mutations were recognizeddemonstrated that muscle fiber conduction

velocities were slowed in patients with Hy-poPP. Studies performed before HypoPPmutations were recognized may have in-cluded subjects with sodium or calciummutations. These early studies demon-strated a universal reduction in musclefiber conduction velocity among HypoPPsubjects (12, 13). HypoPP patients withthe Arg-5283His (14) or Arg-12393His(15) calcium channel mutations had re-

duced muscle fiber conduction velocities,which suggested attenuated membranesodium current.

How Do the Calcium and Sodium Channel

Mutations Relate to the Membrane Abnor-

malities in HypoPP? Understanding howchannel mutations produce the membraneabnormalities that lead to the clinical phe-notype in HypoPP is a challenge. TheTable lists four important features of Hy-poPP. The calcium channel mutations donot directly explain any of the four cardi-nal features of HypoPP, hence the calcium

channel mutations represent an indirectchannelopathy (1618).Some of the prop-erties of HypoPP muscle are directly un-derstood from the sodium channel muta-tions. Episodic hypoglycemia results fromexcessive cellular uptake of potassium,

which may be stimulated by glucose intakeand insulin release (35). Our currentunderstanding of muscle physiology doesnot suggest how the sodium or calciumchannel mutations associated with Hy-poPP lead to exaggerated cellular potas-sium uptake by skeletal muscle.

Paradoxical membrane depolarization

in response to hypokalemia occurs inHypoPP patients with sodium or calciumchannel mutations. In people with Hy-poPP caused by calcium channel mutations,membrane depolarization resulted from hy-pokalemia activating a pathological depo-larizing cationic current and from reducedinward rectifier K channel conductance(16, 18, 19). The pathological depolarizing

current was not blocked by tetrodotoxin orby the dihydropyridine class of calciumchannel blockers (16, 18). The abnormalinward rectifier K conductance was in partbecause of reduced density of ATP-sensitiveK channels (20). Jurkat-Rott et al. (1)demonstrated that HypoPP patients withsodium channel mutations had attenuatedsodium current because of excess inactiva-tion of mutant sodium channels and re-duced density of sodium channels. How-ever, the reduced sodium current does notexplain why the membrane paradoxicallydepolarized in response to hypokalemia.

Insulin potentiates depolarization inpatients with the Arg-5283His calciumchannel mutation by reducing the out-

ward com ponent of the inwar d rectifierK conductance (16, 18). How insulindepolarizes HypoPP fibers with sodiumchannel mutations is not yet known.

Skeletal muscle membrane excitabilityis impaired in HypoPP. HypoPP musclefibers are very susceptible to depolariza-tion-induced inexcitability (35). Theconduction velocities of HypoPP skeletalmuscle fibers are slow (12, 14, 15). Sus-ceptibility to depolarization-inducedparalysis and slow muscle fiber conduc-

tion velocities both suggest impaired so-dium channel function in HypoPP. Somestudies of muscle fiber c onduction veloc-ity were performed before the channelmutations were recognized and likely

Seecompanionarticle on page 9549in issue 17 of volume97.

*Neurology Service 127(W), Cleveland VAMC, 10701 East

Boulevard, Cleveland, OH 44106. E-mail: robert.ruff@

med.va.gov.

Article published online before print: Proc. Natl. Acad. Sci.

USA, 10.1073pnas.170293197. Article and publica-

tion date are at www.pnas.orgcgidoi10.1073

pnas.170293197

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included patients with sodium and cal-cium channel mutations (12, 13). Hy-poPP patients with the Arg-5283His(14) and Arg-12393His (15) calciumchannel mutations have slow skeletalmuscle fiber conduction velocities. Jur-kat-Rott et al. (1) explained the slow

skeletal muscle fiber conduction veloci-ties for HypoPP with sodium channelmutations patients by demonstrating re-duced action potentialrates of rise be-cause of lower sodium current density onisolated muscle fibers. The low sodiumcurrent amplitude resulted from a highsusceptibility to inactivation of the mu-tant sodium channels and reduced totaldensity of sodium channels. The produc-tion and insertion of normal sodiumchannels into the surface membranes ofHypoPP fibers did not compensate forthe reduced sodium current passing

through the mutant sodium channels.The inability of the HypoPP muscle fi-bers to compensate for the reduced so-dium current through mutant channelsraises questions about how skeletal mus-cle fibers regulate sodium channel

production and membrane insertion tocontrol the excitability of the surfacemembrane. Interestingly, the reduced ex-citability of muscle fibers from patients

with HypoPP because of the Arg-5283His calcium channel mutation wasalso associated with reduced sodium cur-

rent amplitude (18). Reduced sodiumcurrent amplitudes resulted from a lowerdensity of sodium channels with no al-teration in the voltage dependence ofsodium channel activation, fast inactiva-tion or slow inactivation. Consequently,the Arg-5283His calcium channel mu-tation reduced the expression or mem-brane trafficking of normal sodium chan-nels via an undetermined mechanism.The commonality of reduced sodiumcurrent amplitude in both forms of Hy-poPP suggests that reduced sodium cur-rent may be an important pathophysio-logical change needed to produce the

phenotype of HypoPP.In summary, Jurkat-Rott et al. (1)

were able to relate several of the patho-physiological characteristics of HypoPPto membrane changes that directly re-sulted from the sodium channel muta-

tions. The mutant channels inactivated athyperpolarized membrane potentialscompared with normal channels, and thesodium current amplitude was reduced inHypoPP fibers. The reduced sodium cur-rent resulted from the susceptibility ofmutant channels to inactivation and areduced density of sodium channels.Given that the HypoPP fibers heteroge-neously expressed normal and mutantsodium channels, the reduced fiber so-dium current suggests that HypoPP fi-bers cannot compensate for the reducedsodium current by enhancing the produc-tion of normal sodium channels. Thediminished sodium current directly ex-plains the reduced excitability of Hy-poPP fibers. The sodium channel muta-tions do not explain why patients withHypoPP caused by sodium channel mu-tations in D2S4 develop episodic hypo-kalemia, why the HypoPP fibers depo-larize in response to hypokalemia, and

why insulin potentiates fiber depolariza-tion and paralysis.

This work was supported by The Office ofResearch and Development, Medical Re-search Service of the Department of VeteransAffairs.

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Table 1. Characteristics of HypoPP because of sodium or calcium channel mutations

Characteristic of

HypoPP

Present with calcium

channel mutations

Present with sodium

channel mutations

Explained by calcium

channel mutations

Explained by sodium

channel mutations

Episodic hypokalemia Yes(68, 21)

Yes(1, 11)

No(16, 17, 2224)

No(1)

Muscle membranedepolarizes in response toreduced extracellular K

Yes(16, 19)

Yes(1)

No(16, 17, 2224)

No(1)

Insulin potentiates

depolarization

Yes

(16, 19, 20, 25)

Yes

(1)

Indirectly via altered impact

of insulin on potassiumconductance(16, 25, 26)

No

(1)

Reduced interictal skeletalmuscle membraneexcitability

Yes(14, 15)

Probably studies performedbefore mutations recognized

(12, 13)

Indirectly via reducedsodium channel density

(18)

Yes(1)

Ruff PNAS August 29, 2000 vol. 97 no. 18 9833