Skip to main content
SpringerLink
Log in

Cav1.1 Channel and Hypokalemic Periodic Paralysis

  • Chapter
  • First Online:
Pathologies of Calcium Channels

  • 1440 Accesses

Abstract

Hypokalaemic periodic paralysis is a rare inherited autosomal dominant neuromuscular disorder due predominantly to dysfunction of the alpha subunit of the Cav1.1 ion channel, although a significant minority of cases are due to dysfunction of another sarcolemmal ion channel, Nav1.4. Hypokalaemic periodic paralysis has been phenotypically described for several centuries but it was not until 1994 that the first causative gene CACNA1S was identified, followed later by a second gene, SCN4A. Electrophysiologic studies attempted to understand how mutations in these genes affected channel function to account for the described phenotype, but early studies were frustratingly inconclusive. Not least because, a satisfactory explanation eluded researchers as to how two ion channels with very different roles could cause the same disease. In 2007, however, an aberrant gating pore current was identified in several Nav1.4 mutations that revolutionised the hypothesis of the pathogenesis of hypokalemic periodic paralysis. In this chapter we review the evolution of our current understanding of this important skeletal muscle channelopathy.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Allott EN, McArdle B (1937) Clin Sci 3:229

    Google Scholar 

  • Bendahhou S, Cummins TR, Griggs RC, Fu YH, Ptácek LJ (2001) Sodium channel inactivation defects are associated with acetazolamide-exacerbated hypokalemic periodic paralysis. Ann Neurol 50(3):417–20

    Google Scholar 

  • Bezanilla F (2002) Voltage sensor movements. J Gen Physiol 120:465–473

    Article  PubMed  CAS  Google Scholar 

  • Biemond A, Daniels AP (1934) Familial periodic paralysis and its transition into spinal muscular atrophy. Brain 57:91–108

    Article  Google Scholar 

  • Brini M (2004) Ryanodine receptor defects in muscle genetic diseases. Biochem Biophys Res Commun 322:1245–1255

    Article  PubMed  CAS  Google Scholar 

  • Bulman DE, Scoggan KA, Van O, Nicolle MW, Hahn AF, Tollar LL et al. (1999) A novel sodium channel mutation in a family with hypokalemic periodic paralysis. Neurology 53:1932−1936

    Google Scholar 

  • Buruma OJ, Bots GT (1978) Myopathy in familial hypokalaemic periodic paralysis independent of paralytic attacks. Acta Neurol Scand 57:171–179

    Article  PubMed  CAS  Google Scholar 

  • Cannon SC (2010) Voltage-sensor mutations in channelopathies of skeletal muscle. J Physiol 588:1887–1895

    Article  PubMed  CAS  Google Scholar 

  • Cannon SC (2007) Physiologic principles underlying ion channelopathies. Neurotherapeutics 4:174–183

    Article  PubMed  CAS  Google Scholar 

  • Carle T, Lhuillier L, Luce S, Sternberg D, Devuyst O, Fontaine B et al (2006) Gating defects of a novel Na+ channel mutant causing hypokalemic periodic paralysis. Biochem Biophys Res Commun 348(2):653–61

    Google Scholar 

  • Catterall WA (1995) Structure and function of voltage-gated ion channels. Annu Rev Biochem 64:493–531

    Article  PubMed  CAS  Google Scholar 

  • Catterall WA (2010) Ion channel voltage sensors: structure, function, and pathophysiology. Neuron 67:915–928

    Article  PubMed  CAS  Google Scholar 

  • Chabrier S, Monnier N, Lunardi J (2008) Early onset of hypokalaemic periodic paralysis caused by a novel mutation of the CACNA1S gene. J Med Genet 45(10):686–8

    Google Scholar 

  • Conn JW, Fajans SS, Louis LH, Streeten DH, Johnson RD (1957) Intermittent aldosteronism in periodic paralysis; dependence of attacks on retention of sodium, and failure to induce attacks by restriction of dietary sodium. Lancet 272:802–805

    Article  PubMed  CAS  Google Scholar 

  • Engel AG, Lambert EH, Rosevear JW, Tauxe WN (1965) Clinical and electromyographic studies in a patient with primary hypokalemic periodic paralysis. Am J Med 38:626–640

    Article  PubMed  CAS  Google Scholar 

  • Favre I, Moczydlowski E, Schild L (1996) On the structural basis for ionic selectivity among Na+, K+, and Ca2+ in the voltage-gated sodium channel. Biophys J 71:3110–3125

    Article  PubMed  CAS  Google Scholar 

  • Finsterer J, Hess B, Jarius C, Stollberger C, Budka H, Mamoli B (1998) Malnutrition-induced hypokalemic myopathy in chronic alcoholism. J Toxicol Clin Toxicol 36:369–373

    Article  PubMed  CAS  Google Scholar 

  • Fontaine B, Vale-Santos J, Jurkat-Rott K, Reboul J, Plassart E, Rime CS et al (1994) Mapping of the hypokalaemic periodic paralysis (HypoPP) locus to chromosome 1q31-32 in three European families. Nat Genet 6:267–272

    Article  PubMed  CAS  Google Scholar 

  • Fouad G, Dalakas M, Servidei S, Mendell JR, Van den BP, Angelini C et al (1997) Genotype-phenotype correlations of DHP receptor alpha 1-subunit gene mutations causing hypokalemic periodic paralysis. Neuromuscul Disord 7:33–38

    Article  PubMed  CAS  Google Scholar 

  • Fournier E, Arzel M, Sternberg D, Vicart S, Laforet P, Eymard B et al (2004) Electromyography guides toward subgroups of mutations in muscle channelopathies. Ann Neurol 56:650–661

    Article  PubMed  CAS  Google Scholar 

  • Francis DG, Rybalchenko V, A, Cannon SC (2011) Leaky sodium channels from voltage sensor mutations in periodic paralysis, but not paramyotonia. Neurology 76:1635–1641

    Article  PubMed  CAS  Google Scholar 

  • Gallant EM (1983) Barium-treated mammalian skeletal muscle: similarities to hypokalaemic periodic paralysis. J Physiol 335:577–590

    PubMed  CAS  Google Scholar 

  • Goldflam S (1890) Ueber eine eigentu¨mliche Form von periodischer familia¨rer, wahrscheinlich auto-intoxicatorischer paralyse. Wien Med Presse 31:1418

    Google Scholar 

  • Griggs RC, Engel WK, Resnick JS (1970) Acetazolamide treatment of hypokalemic periodic paralysis: prevention of attacks and improvement of persistent weakness. Ann Intern Med 73:39–48

    Article  PubMed  CAS  Google Scholar 

  • Hayward LJ, Kim JS, Lee MY, Zhou H, Kim JW, Misra K et al (2008) Targeted mutation of mouse skeletal muscle sodium channel produces myotonia and potassium-sensitive weakness. J Clin Invest 118:1437–1449

    PubMed  CAS  Google Scholar 

  • Hecht ML, Valtysson B, Hogan K (1997) Spinal anesthesia for a patient with a calcium channel mutation causing hypokalemic periodic paralysis. Anesth Analg 84:461–464

    PubMed  CAS  Google Scholar 

  • Heinemann SH, Terlau H, Stuhmer W, Imoto K, Numa S (1992) Calcium channel characteristics conferred on the sodium channel by single mutations. Nature 356:441–443

    Article  PubMed  CAS  Google Scholar 

  • Hong D, Luan X, Chen B, Zheng R, Zhang W, Wang Z et al (2010) Both hypokalaemic and normokalaemic periodic paralysis in different members of a single family with novel R1129Q mutation in SCN4A gene. J Neurol Neurosurg Psychiatry 81(6):703–4

    Google Scholar 

  • Hyland HH (1949) Periodic paralysis. Can Med Assoc J 61:586–588

    PubMed  CAS  Google Scholar 

  • Jurkat-Rott K, Lehmann-Horn F (2007) Do hyperpolarization-induced proton currents contribute to the pathogenesis of hypokalemic periodic paralysis, a voltage sensor channelopathy? J Gen Physiol 130:1–5

    Article  PubMed  Google Scholar 

  • Jurkat-Rott K, Lehmann-Horn F, Elbaz A, Heine R, Gregg RG, Hogan K et al (1994) A calcium channel mutation causing hypokalemic periodic paralysis. Hum Mol Genet 3:1415–1419

    Article  PubMed  CAS  Google Scholar 

  • Jurkat-Rott K, Mitrovic N, Hang C, Kouzmekine A, Iaizzo P, Herzog J et al (2000) Voltage-sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current. Proc Natl Acad Sci USA 97(17):9549–54

    Google Scholar 

  • Jurkat-Rott K, Weber MA, Fauler M, Guo XH, Holzherr BD, Paczulla A et al (2009) K+-dependent paradoxical membrane depolarization and Na+ overload, major and reversible contributors to weakness by ion channel leaks. Proc Natl Acad Sci U S A 106:4036–4041

    Article  PubMed  CAS  Google Scholar 

  • Ke T, Gomez CR, Mateus HE, Castano JA, Wang QK (2009) Novel CACNA1S mutation causes autosomal dominant hypokalemic periodic paralysis in a South American family. J Hum Genet 54:660–664

    Article  PubMed  CAS  Google Scholar 

  • Kil TH, Kim JB (2010) Severe respiratory phenotype caused by a de novo Arg528Gly mutation in the CACNA1S gene in a patient with hypokalemic periodic paralysis. Eur J Paediatr Neurol 14:278–281

    Article  PubMed  Google Scholar 

  • Kim MK, Lee SH, Park MS, Kim BC, Cho KH, Lee MC et al (2004) Mutation screening in Korean hypokalemic periodic paralysis patients: a novel SCN4A Arg672Cys mutation. Neuromuscul Disord 14(11):727–31

    Google Scholar 

  • Kim JB, Lee KY, Hur JK (2005) A Korean family of hypokalemic periodic paralysis with mutation in a voltage-gated calcium channel (R1239G). J Korean Med Sci 20:162–165

    Article  PubMed  Google Scholar 

  • Kuzmenkin A, Muncan V, Jurkat-Rott K, Hang C, Lerche H, Lehmann-Horn F et al (2002) Enhanced inactivation and pH sensitivity of Na(+) channel mutations causing hypokalaemic periodic paralysis type II. Brain 125:835–843

    Article  PubMed  Google Scholar 

  • Lapie P, Goudet C, Nargeot J, Fontaine B, Lory P (1996) Electrophysiological properties of the hypokalaemic periodic paralysis mutation (R528H) of the skeletal muscle alpha 1s subunit as expressed in mouse L cells. FEBS Lett 382(3):244–8

    Google Scholar 

  • Li FF, Li QQ, Tan ZX, Zhang SY, Liu J, Zhao EY et al (2012) A novel mutation in CACNA1S gene associated with hypokalemic periodic paralysis which has a gender difference in the penetrance. J Mol Neurosci 46:378–383

    Article  PubMed  CAS  Google Scholar 

  • Links TP, Zwarts MJ, Wilmink JT, Molenaar WM, Oosterhuis HJ (1990) Permanent muscle weakness in familial hypokalaemic periodic paralysis. Clinical, radiological and pathological aspects. Brain 113(Pt 6):1873–1889

    Article  PubMed  Google Scholar 

  • Matthews E, Hanna MG (2010) Muscle channelopathies: does the predicted channel gating pore offer new treatment insights for hypokalaemic periodic paralysis? J Physiol 588:1879–1886

    Article  PubMed  CAS  Google Scholar 

  • Matthews E, Labrum R, Sweeney MG, Sud R, Haworth A, Chinnery PF et al (2009) Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis. Neurology 72:1544–1547

    Article  PubMed  CAS  Google Scholar 

  • Matthews E, Portaro S, Ke Q, Sud R, Haworth A, Davis MB et al (2011) Acetazolamide efficacy in hypokalemic periodic paralysis and the predictive role of genotype. Neurology 77(22):1960−1964

    Google Scholar 

  • McArdle B (1962) Adynamia episodica hered1taria and its treatment. Brain 85:121–148

    Article  Google Scholar 

  • McManis PG, Lambert EH, Daube JR (1986) The exercise test in periodic paralysis. Muscle Nerve 9:704–710

    Article  PubMed  CAS  Google Scholar 

  • Mikala G, Bahinski A, Yatani A, Tang S, Schwartz A (1993) Differential contribution by conserved glutamate residues to an ion-selectivity site in the L-type Ca2+ channel pore. FEBS Lett 335:265–269

    Article  PubMed  CAS  Google Scholar 

  • Miller TM, da Silva MR, Miller HA, Kwiecinski H, Mendell JR, Tawil R et al (2004) Correlating phenotype and genotype in the periodic paralyses. Neurology 63:1647–1655

    Article  PubMed  CAS  Google Scholar 

  • Morrill JA et al (1999) Effects of mutations causing hypokalaemic periodic paralysis on the skeletal muscle L-type Ca2+ channel expressed in Xenopus laevis oocytes. J Physiol

    Google Scholar 

  • Musgrave W (1727) A periodic palsy. Philos Trans R Soc Lond B Biol Sci 3:33−34

    Google Scholar 

  • Pearson CM (1964) The periodic paralyses: differential features and pathological observations in permanent myopathic weakness. Brain 87:341–354

    Article  PubMed  CAS  Google Scholar 

  • Plassart E, Elbaz A, Santos JV, Reboul J, Lapie P, Chauveau D et al (1994) Genetic heterogeneity in hypokalemic periodic paralysis (hypoPP). Hum Genet 94:551–556

    Article  PubMed  CAS  Google Scholar 

  • Poskanzer DC, Kerr DN (1961) Periodic paralysis with response to spironolactone. Lancet 2:511–513

    Article  PubMed  CAS  Google Scholar 

  • Ptacek LJ, Tawil R, Griggs RC, Engel AG, Layzer RB, Kwiecinski H et al (1994) Dihydropyridine receptor mutations cause hypokalemic periodic paralysis. Cell 77:863–868

    Article  PubMed  CAS  Google Scholar 

  • Resnick JS, Engel WK, Griggs RC, Stam AC (1968) Acetazolamide prophylaxis in hypokalemic periodic paralysis. N Engl J Med 278:582–586

    Article  PubMed  CAS  Google Scholar 

  • Rudel R, Lehmann-Horn F, Ricker K, Kuther G (1984) Hypokalemic periodic paralysis: in vitro investigation of muscle fiber membrane parameters. Muscle Nerve 7:110–120

    Article  PubMed  CAS  Google Scholar 

  • Ruff RL (1999) Insulin acts in hypokalemic periodic paralysis by reducing inward rectifier K+ current. Neurology 53:1556–1563

    Article  PubMed  CAS  Google Scholar 

  • Schipperheyn JJ, Buruma OJ, Voogd PJ (1978) Hypokalaemic periodic paralysis and cardiomyopathy. Acta Neurol Scand 58:374–378

    Article  PubMed  CAS  Google Scholar 

  • Sokolov S, Scheuer T, Catterall WA (2007) Gating pore current in an inherited ion channelopathy. Nature 446:76–78

    Article  PubMed  CAS  Google Scholar 

  • Standen NB, Stanfield PR (1978) A potential and time-dependent blockade of inward rectification in frog skeletal muscle fibres by barium and strontium ions. J Physiol 280:169–191

    PubMed  CAS  Google Scholar 

  • Starace DM, Bezanilla F (2001) Histidine scanning mutagenesis of basic residues of the S4 segment of the shaker k+ channel. J Gen Physiol 117:469–490

    Article  PubMed  CAS  Google Scholar 

  • Sternberg D, Maisonobe T, Jurkat-Rott K, Nicole S, Launay E, Chauveau D et al (2001) Hypokalaemic periodic paralysis type 2 caused by mutations at codon 672 in the muscle sodium channel gene SCN4A. Brain 124:1091–1099

    Article  PubMed  CAS  Google Scholar 

  • Struyk AF, Cannon SC (2007) A Na+channel mutation linked to hypokalemic periodic paralysis exposes a proton-selective gating pore. J Gen Physiol 130:11–20

    Article  PubMed  CAS  Google Scholar 

  • Struyk AF, Cannon SC (2008) Paradoxical depolarization of BA2 + - treated muscle exposed to low extracellular K + : insights into resting potential abnormalities in hypokalemic paralysis. Muscle Nerve 37:326–337

    Article  PubMed  CAS  Google Scholar 

  • Struyk AF, Markin VS, Francis D, Cannon SC (2008) Gating pore currents in DIIS4 mutations of Nav1.4 associated with periodic paralysis: saturation of ion flux and implications for disease pathogenesis. J Gen Physiol 132:447–464

    Article  PubMed  CAS  Google Scholar 

  • Talbot JH (1941) Periodic paralysis, a clinical syndrome. Medicine (Baltimore) 20:85–143

    Google Scholar 

  • Tan SV, Matthews E, Barber M, Burge JA, Rajakulendran S, Fialho D et al (2011) Refined exercise testing can aid DNA-based diagnosis in muscle channelopathies. Ann Neurol 69:328–340

    Article  PubMed  Google Scholar 

  • Tang S, Mikala G, Bahinski A, Yatani A, Varadi G, Schwartz A (1993) Molecular localization of ion selectivity sites within the pore of a human L-type cardiac calcium channel. J Biol Chem 268:13026–13029

    PubMed  CAS  Google Scholar 

  • Tawil R, McDermott MP, Brown R, Jr., Shapiro BC, Ptacek LJ, McManis PG et al (2000) Randomized trials of dichlorphenamide in the periodic paralyses: working Group on periodic paralysis. Ann Neurol 47:46−53

    Google Scholar 

  • Tombola F, Pathak MM, Isacoff EY (2005) Voltage-sensing arginines in a potassium channel permeate and occlude cation-selective pores. Neuron 45:379–388

    Article  PubMed  CAS  Google Scholar 

  • Tricarico D, Barbieri M, Camerino DC (2000) 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 48:304–312

    Article  PubMed  CAS  Google Scholar 

  • Tricarico D, Barbieri M, Mele A, Carbonara G, Camerino DC (2004) Carbonic anhydrase inhibitors are specific openers of skeletal muscle BK channel of K+-deficient rats. FASEB J 18:760–761

    PubMed  CAS  Google Scholar 

  • Tricarico D, Lovaglio S, Mele A, Rotondo G, Mancinelli E, Meola G et al (2008) Acetazolamide prevents vacuolar myopathy in skeletal muscle of K+-depleted rats. Br J Pharmacol 154:183–190

    Article  PubMed  CAS  Google Scholar 

  • Tricarico D, Servidei S, Tonali P, Jurkat-Rott K, Camerino DC (1999) Impairment of skeletal muscle adenosine triphosphate-sensitive K+ channels in patients with hypokalemic periodic paralysis. J Clin Invest 103:675–682

    Article  PubMed  CAS  Google Scholar 

  • Varadi G, Strobeck M, Koch S, Caglioti L, Zucchi C, Palyi G (1999) Molecular elements of ion permeation and selectivity within calcium channels. Crit Rev Biochem Mol Biol 34:181–214

    Article  PubMed  CAS  Google Scholar 

  • Venance SL, Cannon SC, Fialho D, Fontaine B, Hanna MG, Ptacek LJ et al (2006) The primary periodic paralyses: diagnosis, pathogenesis and treatment. Brain 129:8–17

    Article  PubMed  CAS  Google Scholar 

  • Venance SL, Jurkat-Rott K, Lehmann-Horn F, Tawil R (2004) SCN4A-associated hypokalemic periodic paralysis merits a trial of acetazolamide. Neurology 63:1977

    Article  PubMed  CAS  Google Scholar 

  • Viets HR (1951) Periodic paralysis. JAMA 147:595

    Google Scholar 

  • Westphal C (1885) U¨ ber einen merkwu¨rdigen Fall von periodischer La¨hmung aller vier Extremita¨ten mit gleichzeitigem Erlo¨schen der elektrischen Erregbarkeit wa¨hrend der La¨hmung. Berl klinWchenschr 22:489–511

    Google Scholar 

  • Wu F, Mi W, Cannon SC (2013) Bumetanide prevents transient decreases in muscle force in murine hypokalemic periodic paralysis. Neurology 80(12):1110−1116

    Google Scholar 

  • Wu F, Mi W, Hernandez-Ochoa EO, Burns DK, Fu Y, Gray HF et al (2012) A calcium channel mutant mouse model of hypokalemic periodic paralysis. J Clin Invest 122:4580–4591

    Article  PubMed  CAS  Google Scholar 

  • Yang N, George AL Jr, Horn R (1996) Molecular basis of charge movement in voltage-gated sodium channels. Neuron 16:113–122

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular Neuroscience UCL Medical Research Council Centre for Neuromuscular Disease, UCL, Institute of Neurology and National Hospital for Neurology and Neurosurgery Queen Square London, London, UK

    Emma Matthews & Michael G. Hanna

Authors
  1. Emma Matthews
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael G. Hanna
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael G. Hanna .

Editor information

Editors and Affiliations

  1. Hotchkiss Brain Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, Canada

    Norbert Weiss

  2. Department of Neurophysiology and Pharmacology, Medical University Vienna, Vienna, Austria

    Alexandra Koschak

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Matthews, E., Hanna, M.G. (2014). Cav1.1 Channel and Hypokalemic Periodic Paralysis . In: Weiss, N., Koschak, A. (eds) Pathologies of Calcium Channels. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-40282-1_7

Download citation

Publish with us

Policies and ethics

Search

Navigation