Andersen’s syndrome mutants produce a knockdown of inwardly rectifying K+ channel in mouse skeletal muscle in vivo

  • Dina Simkin
  • Gaëlle Robin
  • Serena Giuliano
  • Ana Vukolic
  • Pamela Moceri
  • Nicolas Guy
  • Kay-Dietrich Wagner
  • Alain Lacampagne
  • Bruno Allard
  • Saïd Bendahhou
Regular Article

Abstract

Andersen’s syndrome (AS) is a rare autosomal disorder that has been defined by the triad of periodic paralysis, cardiac arrhythmia, and developmental anomalies. AS has been directly linked to over 40 different autosomal dominant negative loss-of-function mutations in the KCNJ2 gene, encoding for the tetrameric strong inward rectifying K+ channel KIR2.1. While KIR2.1 channels have been suggested to contribute to setting the resting membrane potential (RMP) and to control the duration of the action potential (AP) in skeletal and cardiac muscle, the mechanism by which AS mutations produce such complex pathophysiological symptoms is poorly understood. Thus, we use an adenoviral transduction strategy to study in vivo subcellular distribution of wild-type (WT) and AS-associated mutant KIR2.1 channels in mouse skeletal muscle. We determined that WT and D71V AS mutant KIR2.1 channels are localized to the sarcolemma and the transverse tubules (T-tubules) of skeletal muscle fibers, while the ∆314-315 AS KIR2.1 mutation prevents proper trafficking of the homo- or hetero-meric channel complexes. Whole-cell voltage-clamp recordings in individual skeletal muscle fibers confirmed the reduction of inwardly rectifying K+ current (IK1) after transduction with ∆314-315 KIR2.1 as compared to WT channels. Analysis of skeletal muscle function revealed reduced force generation during isometric contraction as well as reduced resistance to muscle fatigue in extensor digitorum longus muscles transduced with AS mutant KIR2.1. Together, these results suggest that KIR2.1 channels may be involved in the excitation–contraction coupling process required for proper skeletal muscle function. Our findings provide clues to mechanisms associated with periodic paralysis in AS.

Keywords

Andersen’s syndrome KIR2.1 Skeletal muscle Adenovirus Channelopathies 

References

  1. Adrian RH, Bryant SH (1974) On the repetitive discharge in myotonic muscle fibres. J Physiol 240:505–515CrossRefPubMedPubMedCentralGoogle Scholar
  2. Adrian RH, Chandler WK, Hodgkin AL (1970) Voltage clamp experiments in striated muscle fibres. J Physiol 208:607–644CrossRefPubMedPubMedCentralGoogle Scholar
  3. Adrian RH, Marshall MW (1976) Action potentials reconstructed in normal and myotonic muscle fibres. J Physiol 258:125–143CrossRefPubMedPubMedCentralGoogle Scholar
  4. Allen DG, Lamb GD, Westerblad H (2008a) Impaired calcium release during fatigue. J Appl Physiol 104:296-305Google Scholar
  5. Allen DG, Lamb GD, Westerblad H (2008b) Skeletal muscle fatigue: cellular mechanisms. Physiol Rev 88:287-332Google Scholar
  6. Allen DG, Westerblad H (2001) Role of phosphate and calcium stores in muscle fatigue. J Physiol 536:657–665CrossRefPubMedPubMedCentralGoogle Scholar
  7. Allen DG, Westerblad H, Lee JA, Lannergren J (1992) Role of excitation-contraction coupling in muscle fatigue. Sports Med 13:116-126Google Scholar
  8. Almers W (1972) Potassium conductance changes in skeletal muscle and the potassium concentration in the transverse tubules. J Physiol 225:33–56CrossRefPubMedPubMedCentralGoogle Scholar
  9. Andersen ED, Krasilnikoff PA, Overvad H (1971) Intermittent muscular weakness, extrasystoles, and multiple developmental anomalies. A new syndrome? Acta Paediatr Scand 60:559–564CrossRefPubMedGoogle Scholar
  10. Ashcroft FM, Heiny JA, Vergara J (1985) Inward rectification in the transverse tubular system of frog skeletal muscle studied with potentiometric dyes. J Physiol 359:269–291CrossRefPubMedPubMedCentralGoogle Scholar
  11. Ashen MD, O'Rourke B, Kluge KA, Johns DC, Tomaselli GF (1995) Inward rectifier K+ channel from human heart and brain: cloning and stable expression in a human cell line. Am J Phys 268:H506–H511Google Scholar
  12. Ballester LY, Benson DW, Wong B, Law IH, Mathews KD, Vanoye CG, George AL Jr (2006) Trafficking-competent and trafficking-defective KCNJ2 mutations in Andersen syndrome. Hum Mutat 27:388CrossRefPubMedGoogle Scholar
  13. Ballester LY, Vanoye CG, George AL, Jr. (2007) Exaggerated Mg2+ inhibition of Kir2.1 As a consequence of reduced PIP2 sensitivity in Andersen syndrome. Channels (Austin) 1:209-217Google Scholar
  14. Bendahhou S, Donaldson MR, Plaster NM, Tristani-Firouzi M, Fu YH, Ptacek LJ (2003) Defective potassium channel Kir2.1 Trafficking underlies Andersen-Tawil syndrome. J Biol Chem 278:51779–51785CrossRefPubMedGoogle Scholar
  15. Chew TL, Wolf WA, Gallagher PJ, Matsumura F, Chisholm RL (2002) A fluorescent resonant energy transfer-based biosensor reveals transient and regional myosin light chain kinase activation in lamella and cleavage furrows. J Cell Biol 156:543–553CrossRefPubMedPubMedCentralGoogle Scholar
  16. Christe G (1999) Localization of K(+) channels in the tubules of cardiomyocytes as suggested by the parallel decay of membrane capacitance, IK(1) and IK(ATP) during culture and by delayed IK(1) response to barium. J Mol Cell Cardiol 31:2207–2213CrossRefPubMedGoogle Scholar
  17. Citi S, Kendrick-Jones J (1987) Regulation of non-muscle myosin structure and function. BioEssays 7:155–159CrossRefPubMedGoogle Scholar
  18. Clark RB, Tremblay A, Melnyk P, Allen BG, Giles WR, Fiset C (2001) T-tubule localization of the inward-rectifier K(+) channel in mouse ventricular myocytes: a role in K(+) accumulation. J Physiol 537:979–992CrossRefPubMedPubMedCentralGoogle Scholar
  19. Collet C, Pouvreau S, Csernoch L, Allard B, Jacquemond V (2004) Calcium signaling in isolated skeletal muscle fibers investigated under "silicone voltage-clamp" conditions. Cell Biochem Biophys 40:225–236CrossRefPubMedGoogle Scholar
  20. DiFranco M, Yu C, Quinonez M, Vergara JL (2015) Inward rectifier potassium currents in mammalian skeletal muscle fibres. J Physiol 593:1213–1238CrossRefPubMedPubMedCentralGoogle Scholar
  21. Donaldson MR, Jensen JL, Tristani-Firouzi M, Tawil R, Bendahhou S, Suarez WA, Cobo AM, Poza JJ, Behr E, Wagstaff J, Szepetowski P, Pereira S, Mozaffar T, Escolar DM, Fu YH, Ptacek LJ (2003) PIP2 Binding residues of Kir2.1 Are common targets of mutations causing Andersen syndrome. Neurology 60:1811–1816CrossRefPubMedGoogle Scholar
  22. Doupnik CA, Davidson N, Lester HA (1995) The inward rectifier potassium channel family. Curr Opin Neurobiol 5:268–277CrossRefPubMedGoogle Scholar
  23. Dulhunty AF, Haarmann CS, Green D, Laver DR, Board PG, Casarotto MG (2002) Interactions between dihydropyridine receptors and ryanodine receptors in striated muscle. Prog Biophys Mol Biol 79:45–75CrossRefPubMedGoogle Scholar
  24. Endo M (1972) Stretch-induced increase in activation of skinned muscle fibres by calcium. Nat New Biol 237:211–213CrossRefPubMedGoogle Scholar
  25. Fitts RH (1994) Cellular mechanisms of muscle fatigue. Physiol Rev 74:49–94PubMedGoogle Scholar
  26. Fontaine B, Vale-Santos J, Jurkat-Rott K, Reboul J, Plassart E, Rime CS, Elbaz A, Heine R, Guimaraes J, Weissenbach J et al (1994) Mapping of the hypokalaemic periodic paralysis (HypoPP) locus to chromosome 1q31-32 in three European families. Nat Genet 6:267–272CrossRefPubMedGoogle Scholar
  27. Graham FL, Rudy J, Brinkley P (1989) Infectious circular DNA of human adenovirus type 5: regeneration of viral DNA termini from molecules lacking terminal sequences. EMBO J 8:2077–2085PubMedPubMedCentralGoogle Scholar
  28. Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch 391:85–100CrossRefPubMedGoogle Scholar
  29. Hibino H, Inanobe A, Furutani K, Murakami S, Findlay I, Kurachi Y (2010) Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiol Rev 90:291–366CrossRefPubMedGoogle Scholar
  30. Inagaki N, Tsuura Y, Namba N, Masuda K, Gonoi T, Horie M, Seino Y, Mizuta M, Seino S (1995) Cloning and functional characterization of a novel ATP-sensitive potassium channel ubiquitously expressed in rat tissues, including pancreatic islets, pituitary, skeletal muscle, and heart. J Biol Chem 270:5691–5694CrossRefPubMedGoogle Scholar
  31. Kokunai Y, Nakata T, Furuta M, Sakata S, Kimura H, Aiba T, Yoshinaga M, Osaki Y, Nakamori M, Itoh H, Sato T, Kubota T, Kadota K, Shindo K, Mochizuki H, Shimizu W, Horie M, Okamura Y, Ohno K, Takahashi MP (2014) A Kir3.4 Mutation causes Andersen-Tawil syndrome by an inhibitory effect on Kir2.1. Neurology 82:1058–1064CrossRefPubMedGoogle Scholar
  32. Kristensen M, Hansen T, Juel C (2006) Membrane proteins involved in potassium shifts during muscle activity and fatigue. Am J Physiol 290:R766–R772Google Scholar
  33. Lesage F, Fink M, Barhanin J, Lazdunski M, Mattei MG (1995) Assignment of human G-protein-coupled inward rectifier K+ channel homolog GIRK3 gene to chromosome 1q21-q23. Genomics 29:808–809CrossRefPubMedGoogle Scholar
  34. Lim BC, Kim GB, Bae EJ, Noh CI, Hwang H, Kim KJ, Hwang YS, Ko TS, Chae JH (2010) Andersen cardiodysrhythmic periodic paralysis with KCNJ2 mutations: a novel mutation in the pore selectivity filter residue. J Child Neurol 25:490–493CrossRefPubMedGoogle Scholar
  35. Lopatin AN, Nichols CG (2001) Inward rectifiers in the heart: an update on I(K1). J Mol Cell Cardiol 33:625–638CrossRefPubMedGoogle Scholar
  36. Ma D, Taneja TK, Hagen BM, Kim BY, Ortega B, Lederer WJ, Welling PA (2011) Golgi export of the Kir2.1 Channel is driven by a trafficking signal located within its tertiary structure. Cell 145:1102–1115CrossRefPubMedPubMedCentralGoogle Scholar
  37. Miake J, Marban E, Nuss HB (2003) Functional role of inward rectifier current in heart probed by Kir2.1 Overexpression and dominant-negative suppression. J Clin Invest 111:1529–1536CrossRefPubMedPubMedCentralGoogle Scholar
  38. Movsesian MA, Schwinger RH (1998) Calcium sequestration by the sarcoplasmic reticulum in heart failure. Cardiovasc Res 37:352–359CrossRefPubMedGoogle Scholar
  39. Plaster NM, Tawil R, Tristani-Firouzi M, Canun S, Bendahhou S, Tsunoda A, Donaldson MR, Iannaccone ST, Brunt E, Barohn R, Clark J, Deymeer F, George AL Jr, Fish FA, Hahn A, Nitu A, Ozdemir C, Serdaroglu P, Subramony SH, Wolfe G, Fu YH, Ptacek LJ (2001) Mutations in Kir2.1 Cause the developmental and episodic electrical phenotypes of Andersen's syndrome. Cell 105:511–519CrossRefPubMedGoogle Scholar
  40. Priori SG, Pandit SV, Rivolta I, Berenfeld O, Ronchetti E, Dhamoon A, Napolitano C, Anumonwo J, di Barletta MR, Gudapakkam S, Bosi G, Stramba-Badiale M, Jalife J (2005) A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res 96:800–807CrossRefPubMedGoogle Scholar
  41. Raab-Graham KF, Radeke CM, Vandenberg CA (1994) Molecular cloning and expression of a human heart inward rectifier potassium channel. Neuroreport 5:2501–2505CrossRefPubMedGoogle Scholar
  42. Reiken S, Lacampagne A, Zhou H, Kherani A, Lehnart SE, Ward C, Huang F, Gaburjakova M, Gaburjakova J, Rosemblit N, Warren MS, He KL, Yi GH, Wang J, Burkhoff D, Vassort G, Marks AR (2003) PKA phosphorylation activates the calcium release channel (ryanodine receptor) in skeletal muscle: defective regulation in heart failure. J Cell Biol 160:919–928CrossRefPubMedPubMedCentralGoogle Scholar
  43. Ryan DP, da Silva MR, Soong TW, Fontaine B, Donaldson MR, Kung AW, Jongjaroenprasert W, Liang MC, Khoo DH, Cheah JS, Ho SC, Bernstein HS, Maciel RM, Brown RH Jr, Ptacek LJ (2010) Mutations in potassium channel Kir2.6 Cause susceptibility to thyrotoxic hypokalemic periodic paralysis. Cell 140:88–98CrossRefPubMedPubMedCentralGoogle Scholar
  44. Sacco S, Giuliano S, Sacconi S, Desnuelle C, Barhanin J, Amri EZ, Bendahhou S (2014) The inward rectifier potassium channel Kir2.1 is required for osteoblastogenesis. Hum Mol Genet 24:471–479Google Scholar
  45. Sacconi S, Simkin D, Arrighi N, Chapon F, Larroque MM, Vicart S, Sternberg D, Fontaine B, Barhanin J, Desnuelle C, Bendahhou S (2009) Mechanisms underlying Andersen's syndrome pathology in skeletal muscle are revealed in human myotubes. Am J Physiol 297:C876–C885CrossRefGoogle Scholar
  46. Sakura H, Ammala C, Smith PA, Gribble FM, Ashcroft FM (1995a) Cloning and functional expression of the cDNA encoding a novel ATP-sensitive potassium channel subunit expressed in pancreatic beta-cells, brain, heart and skeletal muscle. FEBS Lett 377:338-344Google Scholar
  47. Sakura H, Bond C, Warren-Perry M, Horsley S, Kearney L, Tucker S, Adelman J, Turner R, Ashcroft FM (1995b) Characterization and variation of a human inwardly-rectifying-K-channel gene (KCNJ6): a putative ATP-sensitive K-channel subunit. FEBS Lett 367:193-197Google Scholar
  48. Sejersted OM, Sjogaard G (2000) Dynamics and consequences of potassium shifts in skeletal muscle and heart during exercise. Physiol Rev 80:1411–1481PubMedGoogle Scholar
  49. 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 280:169–191CrossRefPubMedPubMedCentralGoogle Scholar
  50. Stoffel M, Espinosa R 3rd, Powell KL, Philipson LH, Le Beau MM, Bell GI (1994) Human G-protein-coupled inwardly rectifying potassium channel (GIRK1) gene (KCNJ3): localization to chromosome 2 and identification of a simple tandem repeat polymorphism. Genomics 21:254–256CrossRefPubMedGoogle Scholar
  51. Tan SV, Z'Graggen WJ, Boerio D, Rayan DL, Howard R, Hanna MG, Bostock H (2012) Membrane dysfunction in Andersen-Tawil syndrome assessed by velocity recovery cycles. Muscle Nerve 46:193–203CrossRefPubMedGoogle Scholar
  52. Tristani-Firouzi M, Jensen JL, Donaldson MR, Sansone V, Meola G, Hahn A, Bendahhou S, Kwiecinski H, Fidzianska A, Plaster N, Fu YH, Ptacek LJ, Tawil R (2002) Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J Clin Invest 110:381–388CrossRefPubMedPubMedCentralGoogle Scholar
  53. Tucker SJ, James MR, Adelman JP (1995) Assignment of KATP-1, the cardiac ATP-sensitive potassium channel gene (KCNJ5), to human chromosome 11q24. Genomics 28:127–128CrossRefPubMedGoogle Scholar
  54. Vaidyanathan R, Taffet SM, Vikstrom KL, Anumonwo JM (2010) Regulation of cardiac inward rectifier potassium current (I(K1)) by synapse-associated protein-97. J Biol Chem 285:28000–28009CrossRefPubMedPubMedCentralGoogle Scholar
  55. Ward CW, Reiken S, Marks AR, Marty I, Vassort G, Lacampagne A (2003) Defects in ryanodine receptor calcium release in skeletal muscle from post-myocardial infarct rats. FASEB J 17:1517–1519PubMedGoogle Scholar
  56. Yamada T, Mishima T, Sakamoto M, Sugiyama M, Matsunaga S, Wada M (2006) Oxidation of myosin heavy chain and reduction in force production in hyperthyroid rat soleus. J Appl Physiol (1985) 100:1520–1526CrossRefGoogle Scholar
  57. Yang J, Jan YN, Jan LY (1995) Determination of the subunit stoichiometry of an inwardly rectifying potassium channel. Neuron 15:1441–1447CrossRefPubMedGoogle Scholar
  58. Yano H, Philipson LH, Kugler JL, Tokuyama Y, Davis EM, Le Beau MM, Nelson DJ, Bell GI, Takeda J (1994) Alternative splicing of human inwardly rectifying K+ channel ROMK1 mRNA. Mol Pharmacol 45:854–860PubMedGoogle Scholar
  59. Yoon G, Quitania L, Kramer JH, Fu YH, Miller BL, Ptacek LJ (2006) Andersen-Tawil syndrome: definition of a neurocognitive phenotype. Neurology 66:1703–1710CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Dina Simkin
    • 1
    • 2
  • Gaëlle Robin
    • 3
  • Serena Giuliano
    • 1
  • Ana Vukolic
    • 4
  • Pamela Moceri
    • 1
    • 5
  • Nicolas Guy
    • 6
  • Kay-Dietrich Wagner
    • 7
  • Alain Lacampagne
    • 8
  • Bruno Allard
    • 3
  • Saïd Bendahhou
    • 1
  1. 1.UMR 7370 CNRS, LP2M, Laboratoire d’Excellence - ICSTUniversité Côte d’Azur, Faculté de MédecineNiceFrance
  2. 2.Department of Pharmacology, Feinberg School of MedicineNorthwestern UniversityChicagoUSA
  3. 3.UMR CNRS 5534Université Claude Bernard Lyon 1LyonFrance
  4. 4.Institute for Molecular Health ScienceETH ZurichZurichSwitzerland
  5. 5.Service de Cardiologie, Pasteur HospitalCHU de NiceNiceFrance
  6. 6.UMR 7275 CNRS, IPMCUniversité Côte d’AzurValbonneFrance
  7. 7.UMR 7284 CNRS, INSERM, IBVUniversité Côte d’Azur, Faculté de MédecineNiceFrance
  8. 8.INSERM U1046, UMR CNRS 9214Université de Montpellier, CHRU de MontpellierMontpellierFrance

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