Clinical and Experimental Pediatrics

대한소아청소년과학회 (The Korean Pediatric Society)
권호 표지
DOI QR코드

DOI QR Code

The large-conductance calcium-activated potassium channel holds the key to the conundrum of familial hypokalemic periodic paralysis

  • Kim, June-Bum (Department of Pediatrics, Hallym University Hangang Sacred Heart Hospital) ;
  • Kim, Sung-Jo (Department of Biotechnology, Hoseo University) ;
  • Kang, Sun-Yang (Department of Biotechnology, Hoseo University) ;
  • Yi, Jin Woong (Department of Orthopedic Surgery, Konyang University Hospital) ;
  • Kim, Seung-Min (Department of Biological Sciences, Korea Advanced Institute of Science and Technology)
  • 투고 : 2014.01.17
  • 심사 : 2014.06.03
  • 발행 : 2014.10.10
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Purpose: Familial hypokalemic periodic paralysis (HOKPP) is an autosomal dominant channelopathy characterized by episodic attacks of muscle weakness and hypokalemia. Mutations in the calcium channel gene, CACNA1S, or the sodium channel gene, SCN4A, have been found to be responsible for HOKPP; however, the mechanism that causes hypokalemia remains to be determined. The aim of this study was to improve the understanding of this mechanism by investigating the expression of calcium-activated potassium ($K_{Ca}$) channel genes in HOKPP patients. Methods: We measured the intracellular calcium concentration with fura-2-acetoxymethyl ester in skeletal muscle cells of HOKPP patients and healthy individuals. We examined the mRNA and protein expression of KCa channel genes (KCNMA1, KCNN1, KCNN2, KCNN3, and KCNN4) in both cell types. Results: Patient cells exhibited higher cytosolic calcium levels than normal cells. Quantitative reverse transcription polymerase chain reaction analysis showed that the mRNA levels of the $K_{Ca}$ channel genes did not significantly differ between patient and normal cells. However, western blot analysis showed that protein levels of the KCNMA1 gene, which encodes $K_{Ca}$1.1 channels (also called big potassium channels), were significantly lower in the membrane fraction and higher in the cytosolic fraction of patient cells than normal cells. When patient cells were exposed to 50 mM potassium buffer, which was used to induce depolarization, the altered subcellular distribution of BK channels remained unchanged. Conclusion: These findings suggest a novel mechanism for the development of hypokalemia and paralysis in HOKPP and demonstrate a connection between disease-associated mutations in calcium/sodium channels and pathogenic changes in nonmutant potassium channels.

키워드

참고문헌

  1. Kim JB. Channelopathies. Korean J Pediatr 2014;57:1-18. https://doi.org/10.3345/kjp.2014.57.1.1
  2. Kim JB, Kim MH, Lee SJ, Kim DJ, Lee BC. The genotype and clinical phenotype of Korean patients with familial hypokalemic periodic paralysis. J Korean Med Sci 2007;22:946-51. https://doi.org/10.3346/jkms.2007.22.6.946
  3. Wu F, Mi W, Hernandez-Ochoa EO, Burns DK, Fu Y, Gray HF, et al. A calcium channel mutant mouse model of hypokalemic periodic paralysis. J Clin Invest 2012;122:4580-91. https://doi.org/10.1172/JCI66091
  4. Jurkat-Rott K, Weber MA, Fauler M, Guo XH, Holzherr BD, Paczulla A, et al. 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 2009;106:4036-41. https://doi.org/10.1073/pnas.0811277106
  5. Tricarico D, Mele A, Liss B, Ashcroft FM, Lundquist AL, Desai RR, et al. Reduced expression of Kir6.2/SUR2A subunits explains KATP deficiency in K+-depleted rats. Neuromuscul Disord 2008;18:74-80. https://doi.org/10.1016/j.nmd.2007.07.009
  6. Puwanant A, Ruff RL. INa and IKir are reduced in Type 1 hypokalemic and thyrotoxic periodic paralysis. Muscle Nerve 2010;42:315-27. https://doi.org/10.1002/mus.21693
  7. Kim SJ, Lee YJ, Kim JB. Reduced expression and abnormal localization of the K(ATP) channel subunit SUR2A in patients with familial hypokalemic periodic paralysis. Biochem Biophys Res Commun 2010;391:974-8. https://doi.org/10.1016/j.bbrc.2009.11.177
  8. Kim JB, Lee GM, Kim SJ, Yoon DH, Lee YH. Expression patterns of two potassium channel genes in skeletal muscle cells of patients with familial hypokalemic periodic paralysis. Neurol India 2011; 59:527-31. https://doi.org/10.4103/0028-3886.84331
  9. Sausbier M, Hu H, Arntz C, Feil S, Kamm S, Adelsberger H, et al. Cerebellar ataxia and Purkinje cell dysfunction caused by Ca2+-activated K+ channel deficiency. Proc Natl Acad Sci U S A 2004;101:9474-8. https://doi.org/10.1073/pnas.0401702101
  10. Brenner R, Peree GJ, Bonev AD, Eckman DM, Kosek JC, Wiler SW, et al. Vasoregulation by the beta1 subunit of the calcium-activated potassium channel. Nature 2000;407:870-6. https://doi.org/10.1038/35038011
  11. Van Goor F, Li YX, Stojilkovic SS. Paradoxical role of large-conductance calcium-activated K+ (BK) channels in controlling action potential-driven Ca2+ entry in anterior pituitary cells. J Neurosci 2001;21:5902-15.
  12. Shaw PJ, Feske S. Physiological and pathophysiological functions of SOCE in the immune system. Front Biosci (Elite Ed) 2012; 4:2253-68.
  13. Latorre R, Brauchi S. Large conductance Ca2+-activated K+ (BK) channel: activation by Ca2+ and voltage. Biol Res 2006;39:385-401.
  14. Sansone V, Meola G, Links TP, Panzeri M, Rose MR. Treatment for periodic paralysis. Cochrane Database Syst Rev 2008;(1): CD005045.
  15. Kim JB, Chung KW. Novel de novo mutation in the KCNJ2 gene in a patient with Andersen-Tawil syndrome. Pediatr Neurol 2009;41:464-6. https://doi.org/10.1016/j.pediatrneurol.2009.07.010
  16. Park YH, Kim JB. An atypical phenotype of hypokalemic periodic paralysis caused by a mutation in the sodium channel gene SCN4A. Korean J Pediatr 2010;53:909-12. https://doi.org/10.3345/kjp.2010.53.10.909
  17. Song YW, Kim SJ, Heo TH, Kim MH, Kim JB. Normokalemic periodic paralysis is not a distinct disease. Muscle Nerve 2012;46:914-6. https://doi.org/10.1002/mus.23481
  18. Kil TH, Kim JB. 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 2010;14:278-81. https://doi.org/10.1016/j.ejpn.2009.08.004
  19. Dellavalle A, Sampaolesi M, Tonlorenzi R, Tagliafico E, Sacchetti B, Perani L, et al. Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells. Nat Cell Biol 2007;9:255-67. https://doi.org/10.1038/ncb1542
  20. Ghatta S, Nimmagadda D, Xu X, O'Rourke ST. Large-conductance, calcium-activated potassium channels: structural and functional implications. Pharmacol Ther 2006;110:103-16. https://doi.org/10.1016/j.pharmthera.2005.10.007
  21. Torres YP, Morera FJ, Carvacho I, Latorre R. A marriage of convenience: beta-subunits and voltage-dependent K+ channels. J Biol Chem 2007;282:24485-9. https://doi.org/10.1074/jbc.R700022200
  22. Dinardo MM, Camerino G, Mele A, Latorre R, Conte Camerino D, Tricarico D. Splicing of the rSlo gene affects the molecular composition and drug response of Ca2+-activated K+ channels in skeletal muscle. PLoS One 2012;7:e40235. https://doi.org/10.1371/journal.pone.0040235
  23. Bohm RA, Wang B, Brenner R, Atkinson NS. Transcriptional control of Ca(2+)-activated K(+) channel expression: identification of a second, evolutionarily conserved, neuronal promoter. J Exp Biol 2000;203(Pt 4):693-704.
  24. Adelman JP, Shen KZ, Kavanaugh MP, Warren RA, Wu YN, Lagrutta A, et al. Calcium-activated potassium channels expressed from cloned complementary DNAs. Neuron 1992;9:209-16. https://doi.org/10.1016/0896-6273(92)90160-F
  25. Jin P, Weiger TM, Levitan IB. Reciprocal modulation between the alpha and beta 4 subunits of hSlo calcium-dependent potassium channels. J Biol Chem 2002;277:43724-9. https://doi.org/10.1074/jbc.M205795200
  26. Chen L, Bi D, Tian L, McClafferty H, Steeb F, Ruth P, et al. Palmitoylation of the ${\beta}$4-subunit regulates surface expression of large conductance calcium-activated potassium channel splice variants. J Biol Chem 2013;288:13136-44. https://doi.org/10.1074/jbc.M113.461830
  27. Du W, Bautista JF, Yang H, Diez-Sampedro A, You SA, Wang L, et al. Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder. Nat Genet 2005;37:733-8. https://doi.org/10.1038/ng1585
  28. Laumonnier F, Roger S, Guerin P, Molinari F, M'rad R, Cahard D, et al. Association of a functional deficit of the BKCa channel, a synaptic regulator of neuronal excitability, with autism and mental retardation. Am J Psychiatry 2006;163:1622-9. https://doi.org/10.1176/ajp.2006.163.9.1622
  29. Pyott SJ, Meredith AL, Fodor AA, Vazquez AE, Yamoah EN, Aldrich RW. Cochlear function in mice lacking the BK channel alpha, beta1, or beta4 subunits. J Biol Chem 2007;282:3312-24. https://doi.org/10.1074/jbc.M608726200
  30. Seibold MA, Wang B, Eng C, Kumar G, Beckman KB, Sen S, et al. An african-specific functional polymorphism in KCNMB1 shows sex-specific association with asthma severity. Hum Mol Genet 2008;17:2681-90. https://doi.org/10.1093/hmg/ddn168
  31. Meredith AL, Thorneloe KS, Werner ME, Nelson MT, Aldrich RW. Overactive bladder and incontinence in the absence of the BK large conductance Ca2+-activated K+ channel. J Biol Chem 2004;279:36746-52. https://doi.org/10.1074/jbc.M405621200
  32. Tricarico D, Camerino DC. Recent advances in the pathogenesis and drug action in periodic paralyses and related channelopathies. Front Pharmacol 2011;2:8.
  33. Ruff RL. Insulin acts in hypokalemic periodic paralysis by reducing inward rectifier K+ current. Neurology 1999;53:1556-63. https://doi.org/10.1212/WNL.53.7.1556

피인용 문헌

  1. Molecular structure and function of big calcium-activated potassium channels in skeletal muscle: pharmacological perspectives vol.49, pp.6, 2014, https://doi.org/10.1152/physiolgenomics.00121.2016
  2. Atypical periodic paralysis and myalgia : A novel RYR1 phenotype vol.90, pp.5, 2018, https://doi.org/10.1212/wnl.0000000000004894
  3. Autoantibodies for Cardiac Channels and Sudden Cardiac Death and its Relationship to Autoimmune Disorders vol.15, pp.1, 2019, https://doi.org/10.2174/1573403x14666180716095201
  4. Whole exome sequencing identified a heterozygous KCNJ2 missense variant underlying autosomal dominant familial hypokalemic periodic paralysis in a Pakistani family vol.32, pp.12, 2014, https://doi.org/10.1515/jpem-2019-0276
  5. Whole exome sequencing identified a heterozygous KCNJ2 missense variant underlying autosomal dominant familial hypokalemic periodic paralysis in a Pakistani family vol.32, pp.12, 2014, https://doi.org/10.1515/jpem-2019-0276
  6. BK channel openers NS1619 and NS11021 reverse hydrogen peroxide-induced membrane potential changes in skeletal muscle vol.40, pp.5, 2014, https://doi.org/10.1080/10799893.2020.1756324