Leaky channels make weak muscles

Alfred L. George Jr.

J Clin Invest. 2012;122(12):4333-4336. https://doi.org/10.1172/JCI66535.

Commentary

Mutations in the skeletal muscle voltage-gated (CaV1.1) have been associated with hypokalemic periodic paralysis, but how the pathogenesis of this disorder relates to the functional consequences of mutations was unclear. In this issue of the JCI, Wu and colleagues recapitulate the disease by generating a novel knock-in CaV1.1 mutant mouse and use this model to investigate the cellular and molecular features of pathogenesis. They demonstrated an aberrant muscle cell current conducted through the CaV1.1 voltage-sensor domain (gating pore current) that explains an abnormally depolarized muscle membrane and the failure of muscle action potential firing during challenge with agents known to provoke periodic paralysis. Their work advances understanding of molecular and cellular mechanisms underlying an inherited .

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Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, Tennessee, USA.

Mutations in the skeletal muscle voltage-gated calcium channel (CaV1.1) contraction by impairing action potential have been associated with hypokalemic periodic paralysis, but how the firing along the membrane. A characteris- pathogenesis of this disorder relates to the functional consequences of tic symptom of this phenomenon is known mutations was unclear. In this issue of the JCI, Wu and colleagues recapitu- as “periodic paralysis,” a form of paroxys- late the disease by generating a novel knock-in CaV1.1 mutant mouse and use mal weakness that occurs in the absence of this model to investigate the cellular and molecular features of pathogenesis. neuromuscular junction or motor neuron They demonstrated an aberrant muscle cell current conducted through the disease. Periodic paralysis is most often CaV1.1 voltage-sensor domain (gating pore current) that explains an abnor- thought of as an inherited disease, but mally depolarized muscle membrane and the failure of muscle action poten- certain acquired conditions can produce a tial firing during challenge with agents known to provoke periodic paralysis. similar phenotype. Disturbances in plasma Their work advances understanding of molecular and cellular mechanisms potassium ion concentration often accom- underlying an inherited channelopathy. pany bouts of weakness, and the direction of change has been used to classify the con- Ion channels are ubiquitous membrane caused by mutations in that encode dition as hypokalemic, hyperkalemic, or that confer selective ionic perme- these proteins (1–5). These “channelo- normokalemic periodic paralysis (6). These ability to the plasmalemma or intracellular pathies” represent more than 50 human conditions are not lethal, because respira- membranes and enable a wide variety of genetic diseases, including several affect- tory muscles are spared. important physiological processes, includ- ing skeletal muscle contraction, such as Although the clinical features and inher- ing membrane excitability, synaptic trans- the periodic paralyses and nondystrophic itance pattern have been known since the mission, signal transduction, cell volume myotonias (see “Muscle ”). first half of the twentieth century, the regulation, and transcellular ion transport. pathophysiology of periodic paralysis The vital nature of ion channels is reflect- Hypokalemic periodic paralysis remained mysterious until approximately ed by the existence of inherited disorders Plasma membrane channels in skeletal 30 years ago, when investigators in Ger- muscle are essential for the generation and many published their electrophysiologi- propagation of action potentials, leading cal observations on explanted intercostal Conflict of interest: The author has declared that no conflict of interest exists. to release of intracellular calcium through muscle fibers from subjects with periodic Citation for this article: J Clin Invest. 2012; the process of excitation-contraction cou- paralysis (7). These studies revealed that 122(12):4333–4336. doi:10.1172/JCI66535. pling. dysfunction can hinder resting membrane potential was less nega-

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formational changes involving the S6 seg- Muscle channelopathies ment open the ion pore and permit rapid Voltage-gated (NaV1.4; SCN4A) movement of ions through a passageway Hyperkalemic periodic paralysis created by the pore domain. Normokalemic periodic paralysis The highly conserved S4 segment has Hypokalemic periodic paralysis, type 2 received an enormous amount of attention for the past two decades, particularly with Potassium-aggravated regard to the molecular motions that carry Congenital myasthenic syndrome its positive charges through the membrane Muscle (ClC-1; CLCN1) electric field (10, 11). One startling rev- Dominant (Thomsen’s disease) elation regarding sodium and potassium Recessive generalized myotonia (Becker’s myotonia) channels was that the S4 segment becomes 2+ Dihydropyridine receptor/voltage-gated Ca channel (CaV1.1; CACNA1S) accessible to aqueous -modifying Hypokalemic periodic paralysis, type 1 reagents during gating motions (12, 13). susceptibility This observation led to the hypothesis that Inward rectifying (Kir2.1; KCNJ2) S4 segments travel through the membrane Andersen syndrome via a water-filled cavity. Even more intrigu- /Ca2+ release channel (RyR1; RYR1) ing was the observation that histidine sub- Malignant hyperthermia susceptibility stitutions for arginine residues within the S4 segment generate a proton pore that Acetylcholine receptor, α, β, δ, and ε subunits is separate from the main ion permeation Congenital myasthenic syndromes pathway in the pore domain (14). The cur- rent flowing through the voltage-sensor pore (also known as the gating pore) was termed the “omega” or “gating pore” cur- tive in fibers from hypokalemic periodic forming subunit of an L-type voltage-gated rent (Figure 1B). paralysis (HypoPP) subjects compared with calcium channel (CaV1.1), and less com- Because these S4 segment histidine sub- normal muscle. Further, exposure of the monly by SCN4A mutations (2). Although stitutions created unnatural channels, fibers to low extracellular potassium con- both syndromes are associated with notable astute researchers investigating the func- centration evoked a further depolarization, allelic heterogeneity, CACNA1S and SCN4A tional consequences of channelopathy- whereas this condition hyperpolarized nor- mutations associated with HypoPP are associated mutations recognized that this mal muscle membranes. A similar para- clustered within voltage-sensor domains. A mechanism might explain the pathophysi- doxical depolarization was observed after brief digression on the topic of voltage-gat- ology of HypoPP. Specifically, sodium application of insulin. Both hypokalemia ed channel structure and function will help channel mutations associated with HypoPP and insulin treatment rendered the fibers clarify the pathophysiological significance that replace S4 segment arginine residues electrically inexcitable, owing to inactiva- of this mutation clustering. create channels that conduct an anoma- tion of voltage-gated sodium channels by lous inward current at resting membrane the strongly depolarized membrane poten- Voltage-gated channel structure potentials (15–18). The in vivo relevance tial. By contrast, muscle fibers from sub- and function of this mechanism was demonstrated sub- jects with hyperkalemic periodic paralysis The sodium and calcium channels expressed sequently using a mouse model of the dis- (HyperPP) had normal resting membrane in nerve, heart, and muscle belong to a ease (NaV1.4 R669H knock-in), in which an potentials but exhibited depolarization superfamily of ion channels that are gated anomalous inward current was detected in and inexcitability when exposed to elevated (opened and closed) by changes in mem- muscle cells at hyperpolarized potentials extracellular potassium (8). Tetrodotoxin, brane potential (9). The main pore-forming (19). These investigations offered a molecu- a highly specific blocker of voltage-gated α-subunits have a four-fold symmetry con- lar explanation for HypoPP caused by sodi- sodium channels, reversed the depolariza- sisting of structurally homologous domains um channel mutations, but did not address tion occurring in HyperPP fibers but had (D1–D4), each containing four transmem- what happens with the more common calci- no effect on HypoPP muscle. These obser- brane segments that comprise the voltage- um channel mutations. Furthermore, prior vations established fundamental features sensor domain (S1–S4) and a separate pore studies of mutations engineered in human of the pathogenesis of periodic paralysis domain (S5–S6), important for determining CaV1.1 did not reveal a consistent and com- but left unanswered key questions about ion selectivity (Figure 1A). The S4 segment, pelling pattern of channel dysfunction the nature of the depolarizing stimulus in which functions as the main voltage-sensing that would explain the phenotype, in part the hypokalemic variant. element, is amphipathic, with basic amino because of the difficulty of expressing this Advances in the molecular genetics of acids (arginine or lysine) at every third channel in heterologous cell systems. periodic paralysis revealed that HyperPP is position surrounded by hydrophobic resi- caused exclusively by mutations in SCN4A, dues. Activation of voltage-gated channels Calcium channel mutant mice the encoding the skeletal muscle is evoked by a membrane depolarization To address the pathogenesis of HypoPP voltage-gated sodium channel (NaV1.4), that acts to propel the S4 segments in an caused by CACNA1S mutations, Wu and col- whereas HypoPP is caused most often by outward direction away from the negative leagues in the laboratory of Stephen Can- mutations in CACNA1S, encoding the pore- electrostatic cell interior. Subsequent con- non report in this issue of the JCI the inves-

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current rather than ionic current con- ducted through a known ion channel (20). These findings offered a mechanistic link between calcium channel mutation and attacks of muscle weakness. Anomalous gating pore current creates a precarious balance between the inward and outward currents that maintain the membrane potential. Factors such as hypokalemia that transiently depress potassium cur- rents, which are required to maintain a normal resting membrane potential, can render the muscle severely depolarized and, consequently, inexcitable owing to inacti- vation of sodium channels. Now that a common mechanism of evok- ing gating pore current has been established in HypoPP, several new and intriguing ques- tions emerge. Can aberrant gating pore cur- rent be selectively blocked, and would this prevent attacks of paralysis? Do carbonic anhydrase inhibitors such as acetazolamide and dichlorphenamide, which are effective treatments for HypoPP regardless of geno- type, affect gating pore current directly or indirectly? Are there triggering factors that act specifically by potentiating gating pore current? Finally, what is the basis for vacu- olar myopathy, and why is there a sex-biased penetrance of mutations? These and other important questions can now be addressed using the mouse model developed by Wu and colleagues. Although HypoPP was the first channelo- pathy for which aberrant gating pore cur- rent was implicated in disease pathogenesis, Figure 1 many other S4 mutations in voltage-gated Voltage-gated sodium and calcium channel structural domains and location of gating pore. (A) sodium, calcium, and potassium channels Predicted transmembrane topology model of typical voltage-gated sodium or calcium chan- have been found in other inherited disorders nel. The S4 segments within voltage-sensing domains are indicated by a column of plus (+) of membrane excitability, including epilepsy signs. The inset illustrates locations of the separate voltage-sensing and pore domains that are and cardiac arrhythmia syndromes (21). Are repeated four times in the channel protein. (B) A cutaway view showing the pathway through which ionic current or gating pore currents are conducted. The cylinders within the channels rep- some of these conditions also “gating pore- opathies”? A recent study demonstrating resent the S4 segments, and the approximate location of the HypoPP mutation CaV1.1 R528H is indicated. Figure modified from the Journal of General Physiology (23). that an S4 segment mutation in the cardiac sodium channel (NaV1.5 R219H) associated with dilated cardiomyopathy evokes an aber- tigation of a novel knock-in mouse model and paradoxical membrane depolarization rant proton current (22) suggests that this of the disease (20). Mice were generated that evoked by low extracellular potassium or may be a more widespread phenomenon. express the most common human HypoPP by glucose and insulin challenge. Muscle mutation (CaV1.1 R528H), a histidine sub- fibers from homozygous knock-in R528H Acknowledgments stitution for the outermost arginine residue mice exhibited a –15-mV depolarization of The author is supported by grants from the of the D2/S4 segment in CaV1.1. Although the resting membrane potential similar to NIH (HL083374, NS032387). animals did not exhibit spontaneous human HypoPP fibers. In addition, these attacks of weakness, muscle strength was mice exhibited a chronic vacuolar myopa- Address correspondence to: Alfred L. reduced more severely in male mice, consis- thy similar to that observed in patients George Jr., Division of Genetic Medicine, tent with the reduced penetrance in females with this disorder. 529 Light Hall, Vanderbilt University, 2215 observed for human HypoPP (6). Muscles A critical observation made by these Garland Avenue, Nashville, Tennessee from knock-in mice exhibited features investigators was the presence of an anom- 37232-0275, USA. Phone: 615.936.2660; previously observed in human HypoPP alous inward current in mutant mouse Fax: 615.936.2661; E-mail: al.george@ fibers, including reduced contractile force muscle fibers consistent with gating pore vanderbilt.edu.

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1. George AL Jr. Inherited disorders of voltage-gated sodica hereditaria: In vitro investigation of muscle U S A. 2008;105(50):19980–19985. sodium channels. J Clin Invest. 2005;115(8):1990–1999. cell membrane and contraction parameters. Muscle 17. Struyk AF, Cannon SC. A Na+ channel mutation 2. Jurkat-Rott K, Lehmann-Horn F. Muscle channelo- Nerve. 1983;6(2):113–121. linked to hypokalemic periodic paralysis exposes pathies and critical points in functional and genet- 9. Armstrong CM, Hille B. Voltage-gated ion chan- a proton-selective gating pore. J Gen Physiol. 2007; ic studies. J Clin Invest. 2005;115(8):2000–2009. nels and electrical excitability. Neuron. 1998; 130(1):11–20. 3. Meisler MH, Kearney JA. Sodium channel muta- 20(3):371–380. 18. Struyk AF, Markin VS, Francis D, Cannon SC. Gat- tions in epilepsy and other neurological disorders. 10. Swartz KJ. Sensing voltage across lipid membranes. ing pore currents in DIIS4 mutations of NaV1.4 J Clin Invest. 2005;115(8):2010–2017. Nature. 2008;456(7224):891–897. associated with periodic paralysis: saturation of 4. Moss AJ, Kass RS. Long QT syndrome: from chan- 11. Bezanilla F. How membrane proteins sense voltage. ion flux and implications for disease pathogenesis. nels to cardiac arrhythmias. J Clin Invest. 2005; Nature Rev Mol Cell Biol. 2008;9(4):323–332. J Gen Physiol. 2008;132(4):447–464. 115(8):2018–2024. 12. Yang NB, George AL Jr, Horn R. Molecular basis of 19. Wu F, et al. A sodium channel knockin mutant 5. Jentsch TJ, Maritzen T, Zdebik AA. Chloride chan- charge movement in voltage-gated sodium chan- (NaV1.4-R669H) mouse model of hypokalemic peri- nel diseases resulting from impaired transepithe- nels. Neuron. 1996;16(1):113–122. odic paralysis. J Clin Invest. 2011;121(10):4082–4094. lial transport or vesicular function. J Clin Invest. 13. Larsson HP, Baker OS, Dhillon DS, Isacoff EY. 20. Wu F, et al. A calcium channel mutant mouse 2005;115(8):2039–2046. Transmembrane movement of the K+ chan- model of hypokalemic periodic paralysis. J Clin 6. Cannon SC, George AL. Pathophysiology of myoto- nel S4. Neuron. 1996;16(2):387–397. Invest. 2012;122(12):4580–4591. nia and periodic paralysis. In: Asbury AK, Mckhann 14. Starace DM, Stefani E, Bezanilla F. Voltage-depen- 21. Jurkat-Rott K, Groome J, Lehmann-Horn F. Patho- GM, McDonald WI, Goadsby PJ, McArthur JC, eds. dent proton transport by the voltage sensor of the physiological role of omega pore current in chan- Diseases of the Nervous System, Clinical Neuroscience and shaker K+ channel. Neuron. 1997;19(6):1319–1327. nelopathies. Front Pharmacol. 2012;3:112. Therapeutic Principles. 3rd ed. Cambridge, United King- 15. Sokolov S, Scheuer T, Catterall WA. Gating pore 22. Gosselin-Badaroudine P, et al. A Proton Leak cur- dom: Cambridge University Press; 2002:1183–1206. current in an inherited ion channelopathy. Nature. rent through the cardiac sodium channel is linked 7. Rüdel R, Lehmann-Horn F, Ricker K, Kuther G. 2007;446(7131):76–78. to mixed arrhythmia and the dilated cardiomyopa- Hypokalemic periodic paralysis: in vitro investiga- 16. Sokolov S, Scheuer T, Catterall WA. Depolariza- thy phenotype. PLoS One. 2012;7(5):e38331. tion of muscle fiber membrane parameters. Muscle tion-activated gating pore current conducted by 23. Ahern CA, Horn R. Specificity of charge-carrying Nerve. 1984;7(2):110–120. mutant sodium channels in potassium-sensitive residues in the voltage sensor of potassium chan- 8. Lehmann-Horn F, et al. Two cases of adynamia epi- normokalemic periodic paralysis. Proc Natl Acad Sci nels. J Gen Physiol. 2004;123(3):205–216.

αKlotho: FGF23 coreceptor and FGF23-regulating hormone Harald Jüppner1 and Myles Wolf2

1Endocrine Unit and Pediatric Nephrology Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. 2Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA.

Low levels of phosphate can disrupt bone ossification and predispose to severe hyperphosphatemia, elevated levels of fractures. FGF23 is one of the major determinants of phosphate homeosta- 1,25D, hypercalcemia, diffuse soft tissue cal- sis, acting to increase urinary phosphate excretion. However, the regulation cifications, accelerated aging, and premature of FGF23 is incompletely understood. In this issue of the JCI, Smith et al. death (6). These findings are largely indistin- show that the cleaved form of αKlotho, the membrane-bound form of which guishable from those observed in FGF23 is an FGF23 coreceptor, serves as a novel endocrine regulator of phosphate loss-of-function models (7, 8). homeostasis, capable of inducing FGF23 production in osteocytes. Osteocytes are the primary cellular source of FGF23 after the fetal period Phosphate is a critical component of bone, um-dependent phosphate cotransport- (9), but little is known about their regu- and it serves numerous biological functions ers, NPT2a and NPT2c, thereby lowering lation and secretion. Although discovery in the synthesis of DNA and membrane lip- serum phosphate levels. However, in con- of the molecular causes of monogenic ids, protein modifications, energy metabo- trast to FGF23, which decreases serum lev- hypophosphatemic rickets disorders has lism, and second messenger formation. els of 1,25-dihydroxyvitamin D (1,25D) by helped to identify a set of bone-derived FGF23 and parathyroid hormone (PTH) inhibiting renal 1α-hydroxylase and stimu- proteins that decrease FGF23 production, are the major regulators of phosphate lating 24-hydroxylase, PTH increases renal the mechanisms of how these inhibitors homeostasis (1, 2). Both hormones increase production of 1,25D, which consequently suppress FGF23 remain largely unknown. urinary phosphate excretion by reducing enhances the absorption of phosphate (and Furthermore, despite our knowledge that proximal tubular expression of the sodi- calcium) from the intestinal tract (3). changes in dietary phosphate intake can FGF23 belongs to the subfamily of endo- alter FGF23 levels in healthy individuals Conflict of interest: Myles Wolf has received research crine FGFs and mediates its phosphate- (10, 11), how serum phosphate or phos- support or honoraria from Abbott Laboratories, Amgen, DiaSorin, Kai Pharmaceuticals, Luitpold Phar- regulating actions in the kidney through phate balance is sensed and how this signal maceuticals Inc., Mitsubishi, Sanofi, and Shire. Harald FGF receptors (FGFRs), most prominently is conveyed to the osteocyte to alter FGF23 Jüppner has received honoraria from Kai Pharmaceu- FGFR1. These actions require the transmem- expression remains completely unknown. ticals, Roche, Kyowa Hakko Kirin, Genzyme, Amgen, brane form of αKlotho (mKL), which acts and Pfizer; he is a coinventor of a patent describing a technique to measure FGF23. as the coreceptor that enhances the bind- A novel regulator of FGF23 synthesis Citation for this article: J Clin Invest. 2012; ing affinity of FGF23 to different FGFRs In this issue of the JCI, Smith et al. pro- 122(12):4336–4339. doi:10.1172/JCI67055. (4, 5). Ablation of αKlotho in mice leads to vide intriguing new findings about the

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