Clinical and Experimental Pediatrics

The Korean Pediatric Society (대한소아청소년과학회)
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Channelopathies

  • Kim, June-Bum (Department of Pediatrics, Seoul Children's Hospital)
  • Received : 2013.08.05
  • Accepted : 2013.10.04
  • Published : 2014.01.15
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Abstract

Channelopathies are a heterogeneous group of disorders resulting from the dysfunction of ion channels located in the membranes of all cells and many cellular organelles. These include diseases of the nervous system (e.g., generalized epilepsy with febrile seizures plus, familial hemiplegic migraine, episodic ataxia, and hyperkalemic and hypokalemic periodic paralysis), the cardiovascular system (e.g., long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia), the respiratory system (e.g., cystic fibrosis), the endocrine system (e.g., neonatal diabetes mellitus, familial hyperinsulinemic hypoglycemia, thyrotoxic hypokalemic periodic paralysis, and familial hyperaldosteronism), the urinary system (e.g., Bartter syndrome, nephrogenic diabetes insipidus, autosomal-dominant polycystic kidney disease, and hypomagnesemia with secondary hypocalcemia), and the immune system (e.g., myasthenia gravis, neuromyelitis optica, Isaac syndrome, and anti-NMDA [N-methyl-D-aspartate] receptor encephalitis). The field of channelopathies is expanding rapidly, as is the utility of molecular-genetic and electrophysiological studies. This review provides a brief overview and update of channelopathies, with a focus on recent advances in the pathophysiological mechanisms that may help clinicians better understand, diagnose, and develop treatments for these diseases.

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References

  1. Ashcroft FM. From molecule to malady. Nature 2006;440:440-7. https://doi.org/10.1038/nature04707
  2. Valverde MA, Cantero-Recasens G, Garcia-Elias A, Jung C, Carreras- Sureda A, Vicente R. Ion channels in asthma. J Biol Chem 2011; 286:32877-82. https://doi.org/10.1074/jbc.R110.215491
  3. Saito YA, Strege PR, Tester DJ, Locke GR III, Talley NJ, Bernard CE, et al. Sodium channel mutation in the irritable bowel syndrome: Evidence for an ion channelopathy. Am J Physiol Gastrointest Liver Physiol 2009;296:G211-8. https://doi.org/10.1152/ajpgi.90571.2008
  4. Hille B. Ion Channels of Excitable Membranes. 3rd ed. Massachusetts: Sinauer Associates, 2001.
  5. Coetzee WA, Amarillo Y, Chiu J, Chow A, Lau D, McCormack T, et al. Molecular diversity of K+ channels. Ann N Y Acad Sci 1999; 868:233-85. https://doi.org/10.1111/j.1749-6632.1999.tb11293.x
  6. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 2010;51:676-85. https://doi.org/10.1111/j.1528-1167.2010.02522.x
  7. Lehmann-Horn F, Jurkat-Rott K. Voltage-gated ion channels and hereditary disease. Physiol Rev 1999;79:1317-72.
  8. 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
  9. Tricarico D, Camerino DC. Recent advances in the pathogenesis and drug action in periodic paralyses and related channelopathies. Front Pharmacol 2011;2:8.
  10. 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
  11. 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
  12. Levitt LP, Rose LI, Dawson DM. Hypokalemic periodic paralysis with arrhythmia. N Engl J Med 1972;286:253-4. https://doi.org/10.1056/NEJM197202032860507
  13. Wu F, Mi W, Hernández-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
  14. 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
  15. 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
  16. Kim SJ, Lee YJ, Kim JB. Reduced expression and abnormal localization of the KATP 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
  17. 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
  18. Ballester LY, Benson DW, Wong B, Law IH, Mathews KD, Vanoye CG, et al. Trafficking-competent and trafficking-defective KCNJ2 mutations in Andersen syndrome. Hum Mutat 2006;27:388.
  19. Engel AG. Current status of the congenital myasthenic syndromes. Neuromuscul Disord 2012;22:99-111. https://doi.org/10.1016/j.nmd.2011.10.009
  20. Scheffer IE, Zhang YH, Jansen FE, Dibbens L. Dravet syndrome or genetic (generalized) epilepsy with febrile seizures plus? Brain Dev 2009;31:394-400. https://doi.org/10.1016/j.braindev.2009.01.001
  21. Huang X, Tian M, Hernandez CC, Hu N, Macdonald RL. The GABRG2 nonsense mutation, Q40X, associated with Dravet syndrome activated NMD and generated a truncated subunit that was partially rescued by aminoglycoside-induced stop codon read-through. Neurobiol Dis 2012;48:115-23. https://doi.org/10.1016/j.nbd.2012.06.013
  22. Maljevic S, Krampfl K, Cobilanschi J, Tilgen N, Beyer S, Weber YG, et al. A mutation in the GABAA receptor $\alpha{1}$-subunit is associated with absence epilepsy. Ann Neurol 2006;59:983-7. https://doi.org/10.1002/ana.20874
  23. Hernandez CC, Gurba KN, Hu N, Macdonald RL. The GABRA6 mutation, R46W, associated with childhood absence epilepsy, alters $\alpha{6}\beta{2}\gamma{2}$ and $\alpha{6}\beta{2}\delta$ GABAA receptor channel gating and expression. J Physiol 2011;589:5857-78. https://doi.org/10.1113/jphysiol.2011.218883
  24. Tanaka M, Olsen RW, Medina MT, Schwartz E, Alonso ME, Duron RM, et al. Hyperglycosylation and reduced GABA currents of mutated GABRB3 polypeptide in remitting childhood absence epilepsy. Am J Hum Genet 2008;82:1249-61. https://doi.org/10.1016/j.ajhg.2008.04.020
  25. Tian M, Macdonald RL. The intronic GABRG2 mutation, IVS6+2T$\rightarrow$G, associated with childhood absence epilepsy altered subunit mRNA intron splicing, activated nonsense-mediated decay, and produced a stable truncated $\gamma{2}$ subunit. J Neurosci 2012;32:5937-52. https://doi.org/10.1523/JNEUROSCI.5332-11.2012
  26. Tottene A, Urbani A, Pietrobon D. Role of different voltage-gated Ca2+ channels in cortical spreading depression: specific requirement of P/Q-type Ca2+ channels. Channels (Austin) 2011;5:110-4. https://doi.org/10.4161/chan.5.2.14149
  27. Rajakulendran S, Graves TD, Labrum RW, Kotzadimitriou D, Eunson L, Davis MB, et al. Genetic and functional characterisation of the P/Q calcium channel in episodic ataxia with epilepsy. J Physiol 2010; 588:1905-13. https://doi.org/10.1113/jphysiol.2009.186437
  28. Unno T, Wakamori M, Koike M, Uchiyama Y, Ishikawa K, Kubota H, et al. Development of Purkinje cell degeneration in a knockin mouse model reveals lysosomal involvement in the pathogenesis of SCA6. Proc Natl Acad Sci U S A 2012;109:17693-8. https://doi.org/10.1073/pnas.1212786109
  29. Heron SE, Smith KR, Bahlo M, Nobili L, Kahana E, Licchetta L, et al. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 2012;44:1188-90. https://doi.org/10.1038/ng.2440
  30. Rodrigues-Pinguet N, Jia L, Li M, Figl A, Klaassen A, Truong A, et al. Five ADNFLE mutations reduce the Ca2+ dependence of the mammalian $\alpha{4}\beta{2}$ acetylcholine response. J Physiol 2003;550:11-26. https://doi.org/10.1113/jphysiol.2003.036681
  31. Chung SK, Vanbellinghen JF, Mullins JG, Robinson A, Hantke J, Hammond CL, et al. Pathophysiological mechanisms of dominant and recessive GLRA1 mutations in hyperekplexia. J Neurosci 2010; 30:9612-20. https://doi.org/10.1523/JNEUROSCI.1763-10.2010
  32. Bockenhauer D, Feather S, Stanescu HC, Bandulik S, Zdebik AA, Reichold M, et al. Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations. N Engl J Med 2009;360:1960-70. https://doi.org/10.1056/NEJMoa0810276
  33. Scholl UI, Choi M, Liu T, Ramaekers VT, Häusler MG, Grimmer J, et al. Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10. Proc Natl Acad Sci U S A 2009;106:5842-7. https://doi.org/10.1073/pnas.0901749106
  34. Kremeyer B, Lopera F, Cox JJ, Momin A, Rugiero F, Marsh S, et al. A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome. Neuron 2010;66:671-80. https://doi.org/10.1016/j.neuron.2010.04.030
  35. Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature 2006;444:894-8. https://doi.org/10.1038/nature05413
  36. Nilius B, Voets T. The puzzle of TRPV4 channelopathies. EMBO Rep 2013;14:152-63. https://doi.org/10.1038/embor.2012.219
  37. Curcio-Morelli C, Zhang P, Venugopal B, Charles FA, Browning MF, Cantiello HF, et al. Functional multimerization of mucolipin channel proteins. J Cell Physiol 2010;222:328-35. https://doi.org/10.1002/jcp.21956
  38. Amin AS, Tan HL, Wilde AA. Cardiac ion channels in health and disease. Heart Rhythm 2010;7:117-26. https://doi.org/10.1016/j.hrthm.2009.08.005
  39. Behr ER, Dalageorgou C, Christiansen M, Syrris P, Hughes S, Tome Esteban MT, et al. Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the majority of families. Eur Heart J 2008;29:1670-80. https://doi.org/10.1093/eurheartj/ehn219
  40. Wilders R. Cardiac ion channelopathies and the sudden infant death syndrome. ISRN Cardiol 2012;2012:846171.
  41. Campuzano O, Beltrán-Alvarez P, Iglesias A, Scornik F, Pérez G, Brugada R. Genetics and cardiac channelopathies. Genet Med 2010;12:260-7. https://doi.org/10.1097/GIM.0b013e3181d81636
  42. Yang Y, Yang Y, Liang B, Liu J, Li J, Grunnet M, et al. Identification of a Kir3.4 mutation in congenital long QT syndrome. Am J Hum Genet 2010;86:872-80. https://doi.org/10.1016/j.ajhg.2010.04.017
  43. Templin C, Ghadri JR, Rougier JS, Baumer A, Kaplan V, Albesa M, et al. Identification of a novel loss-of-function calcium channel gene mutation in short QT syndrome (SQTS6). Eur Heart J 2011;32:1077-88. https://doi.org/10.1093/eurheartj/ehr076
  44. Wilde AA, Brugada R. Phenotypical manifestations of mutations in the genes encoding subunits of the cardiac sodium channel. Circ Res 2011;108:884-97. https://doi.org/10.1161/CIRCRESAHA.110.238469
  45. Olson TM, Alekseev AE, Liu XK, Park S, Zingman LV, Bienengraeber M, et al. Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation. Hum Mol Genet 2006;15:2185-91. https://doi.org/10.1093/hmg/ddl143
  46. Biel M, Wahl-Schott C, Michalakis S, Zong X. Hyperpolarization-activated cation channels: from genes to function. Physiol Rev 2009;89:847-85. https://doi.org/10.1152/physrev.00029.2008
  47. Duhme N, Schweizer PA, Thomas D, Becker R, Schröter J, Barends TR, et al. Altered HCN4 channel C-linker interaction is associated with familial tachycardia-bradycardia syndrome and atrial fibrillation. Eur Heart J 2013;34:2768-75.
  48. Ueda K, Hirano Y, Higashiuesato Y, Aizawa Y, Hayashi T, Inagaki N, et al. Role of HCN4 channel in preventing ventricular arrhythmia. J Hum Genet 2009;54:115-21. https://doi.org/10.1038/jhg.2008.16
  49. Postma AV, Denjoy I, Kamblock J, Alders M, Lupoglazoff JM, Vaksmann G, et al. Catecholaminergic polymorphic ventricular tachycardia: RYR2 mutations, bradycardia, and follow up of the patients. J Med Genet 2005;42:863-70. https://doi.org/10.1136/jmg.2004.028993
  50. van der Werf C, Wilde AA. Catecholaminergic polymorphic ventricular tachycardia: from bench to bedside. Heart 2013;99:497-504. https://doi.org/10.1136/heartjnl-2012-302033
  51. Davies JC, Alton EW, Bush A. Cystic fibrosis. BMJ 2007;335:1255-9. https://doi.org/10.1136/bmj.39391.713229.AD
  52. Ratjen FA. Cystic fibrosis: pathogenesis and future treatment strategies. Respir Care 2009;54:595-605. https://doi.org/10.4187/aarc0427
  53. Sweeney M, McDaniel SS, Platoshyn O, Zhang S, Yu Y, Lapp BR, et al. Role of capacitative Ca2+ entry in bronchial contraction and remodeling. J Appl Physiol 2002;92:1594-602. https://doi.org/10.1152/japplphysiol.00722.2001
  54. So SY, Ip M, Lam WK. Calcium channel blockers and asthma. Lung 1986;164:1-16. https://doi.org/10.1007/BF02713625
  55. Xiao JH, Zheng YM, Liao B, Wang YX. Functional role of canonical transient receptor potential 1 and canonical transient receptor potential 3 in normal and asthmatic airway smooth muscle cells. Am J Respir Cell Mol Biol 2010;43:17-25. https://doi.org/10.1165/rcmb.2009-0091OC
  56. Sel S, Rost BR, Yildirim AO, Sel B, Kalwa H, Fehrenbach H, et al. Loss of classical transient receptor potential 6 channel reduces allergic airway response. Clin Exp Allergy 2008;38:1548-58. https://doi.org/10.1111/j.1365-2222.2008.03043.x
  57. Vennekens R, Olausson J, Meissner M, Bloch W, Mathar I, Philipp SE, et al. Increased IgE-dependent mast cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective cation channel TRPM4. Nat Immunol 2007;8:312-20. https://doi.org/10.1038/ni1441
  58. Lee LY, Gu Q. Role of TRPV1 in inflammation-induced airway hypersensitivity. Curr Opin Pharmacol 2009;9:243-9. https://doi.org/10.1016/j.coph.2009.02.002
  59. Caceres AI, Brackmann M, Elia MD, Bessac BF, del Camino D, D'Amours M, et al. A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma. Proc Natl Acad Sci U S A 2009;106:9099-104. https://doi.org/10.1073/pnas.0900591106
  60. Akhabir L, Sandford AJ. Genome-wide association studies for discovery of genes involved in asthma. Respirology 2011;16:396-406. https://doi.org/10.1111/j.1440-1843.2011.01939.x
  61. Mahn K, Hirst SJ, Ying S, Holt MR, Lavender P, Ojo OO, et al. Diminished sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) expression contributes to airway remodeling in bronchial asthma. Proc Natl Acad Sci U S A 2009;106:10775-80. https://doi.org/10.1073/pnas.0902295106
  62. Webster R, Maxwell S, Spearman H, Tai K, Beckstein O, Sansom M, et al. A novel congenital myasthenic syndrome due to decreased acetylcholine receptor ion-channel conductance. Brain 2012;135: 1070-80. https://doi.org/10.1093/brain/aws016
  63. Pyo JY, Joh DH, Park JS, Lee SJ, Lee H, Kim W, et al. Ventricular tachyarrhythmias in a patient with Andersen-Tawil syndrome. Korean Circ J 2013;43:62-5. https://doi.org/10.4070/kcj.2013.43.1.62
  64. Ashcroft FM, Rorsman P. Electrophysiology of the pancreatic $\beta$-cell. Prog Biophys Mol Biol 1989;54:87-143. https://doi.org/10.1016/0079-6107(89)90013-8
  65. Vivaudou M, Moreau CJ, Terzic A. Structure and function of ATP-sensitive K+ channels. In: Kew J, Davies C, editors. Ion channels: from structure to function. 1st ed. Oxford: Oxford University Press, 2009:454-73.
  66. Babenko AP, Polak M, Cave H, Busiah K, Czernichow P, Scharfmann R, et al. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med 2006;355:456-66. https://doi.org/10.1056/NEJMoa055068
  67. Kong JH, Kim JB. Transient neonatal diabetes mellitus caused by a de novo ABCC8 gene mutation. Korean J Pediatr 2011;54:179-82. https://doi.org/10.3345/kjp.2011.54.4.179
  68. Koster JC, Permutt MA, Nichols CG. Diabetes and insulin secretion: the ATP-sensitive K+ channel (KATP) connection. Diabetes 2005; 54:3065-72. https://doi.org/10.2337/diabetes.54.11.3065
  69. Ashcroft FM. ATP-sensitive potassium channelopathies: focus on insulin secretion. J Clin Invest 2005;115:2047-58. https://doi.org/10.1172/JCI25495
  70. Ryan DP, da Silva MR, Soong TW, Fontaine B, Donaldson MR, Kung AW, et al. Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis. Cell 2010;140:88-98. https://doi.org/10.1016/j.cell.2009.12.024
  71. 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
  72. Scholl UI, Nelson-Williams C, Yue P, Grekin R, Wyatt RJ, Dillon MJ, et al. Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5. Proc Natl Acad Sci U S A 2012;109:2533-8. https://doi.org/10.1073/pnas.1121407109
  73. Del Fattore A, Cappariello A, Teti A. Genetics, pathogenesis and complications of osteopetrosis. Bone 2008;42:19-29. https://doi.org/10.1016/j.bone.2007.08.029
  74. Schaller S, Henriksen K, Sveigaard C, Heegaard AM, Hélix N, Stahlhut M, et al. The chloride channel inhibitor NS3736 [corrected] prevents bone resorption in ovariectomized rats without changing bone formation. J Bone Miner Res 2004;19:1144-53. https://doi.org/10.1359/JBMR.040302
  75. Riepe FG. Clinical and molecular features of type 1 pseudohypoaldosteronism. Horm Res 2009;72:1-9.
  76. Butterworth MB. Regulation of the epithelial sodium channel (ENaC) by membrane trafficking. Biochim Biophys Acta 2010;1802:1166-77. https://doi.org/10.1016/j.bbadis.2010.03.010
  77. Moeller HB, Rittig S, Fenton RA. Nephrogenic diabetes insipidus: essential insights into the molecular background and potential therapies for treatment. Endocr Rev 2013;34:278-301. https://doi.org/10.1210/er.2012-1044
  78. Kleta R, Bockenhauer D. Bartter syndromes and other salt-losing tubulopathies. Nephron Physiol 2006;104:73-80. https://doi.org/10.1159/000094001
  79. Schlingmann KP, Waldegger S, Konrad M, Chubanov V, Gudermann T. TRPM6 and TRPM7-Gatekeepers of human magnesium metabolism. Biochim Biophys Acta 2007;1772:813-21. https://doi.org/10.1016/j.bbadis.2007.03.009
  80. Dryer SE, Reiser J. TRPC6 channels and their binding partners in podocytes: role in glomerular filtration and pathophysiology. Am J Physiol Renal Physiol 2010;299:F689-701. https://doi.org/10.1152/ajprenal.00298.2010
  81. Miyakawa A, Ibarra C, Malmersjö S, Aperia A, Wiklund P, Uhlén P. Intracellular calcium release modulates polycystin-2 trafficking. BMC Nephrol 2013;14:34. https://doi.org/10.1186/1471-2369-14-34
  82. Zaika O, Mamenko M, Berrout J, Boukelmoune N, O'Neil RG, Pochynyuk O. TRPV4 dysfunction promotes renal cystogenesis in autosomal recessive polycystic kidney disease. J Am Soc Nephrol 2013;24:604-16. https://doi.org/10.1681/ASN.2012050442
  83. Kleopa KA. Autoimmune channelopathies of the nervous system. Curr Neuropharmacol 2011;9:458-67. https://doi.org/10.2174/157015911796557966
  84. Vincent A. Developments in autoimmune channelopathies. Autoimmun Rev 2013;12:678-81. https://doi.org/10.1016/j.autrev.2012.10.016
  85. Verschuuren JJ, Huijbers MG, Plomp JJ, Niks EH, Molenaar PC, Martinez-Martinez P, et al. Pathophysiology of myasthenia gravis with antibodies to the acetylcholine receptor, muscle-specific kinase and low-density lipoprotein receptor-related protein 4. Autoimmun Rev 2013;12:918-23. https://doi.org/10.1016/j.autrev.2013.03.001
  86. Winston N, Vernino S. Recent advances in autoimmune autonomic ganglionopathy. Curr Opin Neurol 2010;23:514-8. https://doi.org/10.1097/WCO.0b013e32833d4c7f
  87. Titulaer MJ, Lang B, Verschuuren J. Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol 2011;10:1098-107. https://doi.org/10.1016/S1474-4422(11)70245-9
  88. Vincent A, Bien CG, Irani SR, Waters P. Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol 2011;10:759-72. https://doi.org/10.1016/S1474-4422(11)70096-5
  89. Tomimitsu H, Arimura K, Nagado T, Watanabe O, Otsuka R, Kurono A, et al. Mechanism of action of voltage-gated K+ channel antibodies in acquired neuromyotonia. Ann Neurol 2004;56:440-4. https://doi.org/10.1002/ana.20221
  90. Liewluck T, Klein CJ, Jones LK Jr. Cramp-fasciculation syndrome in patients with and without neural autoantibodies. Muscle Nerve 2013 Jul 8 [Epub]. http://dx.doi.org/10.1002/mus.23935.
  91. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice- Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 2011;10:63-74. https://doi.org/10.1016/S1474-4422(10)70253-2
  92. Lauvsnes MB, Omdal R. Systemic lupus erythematosus, the brain, and anti-NR2 antibodies. J Neurol 2012;259:622-9. https://doi.org/10.1007/s00415-011-6232-5
  93. Ratelade J, Verkman AS. Neuromyelitis optica: aquaporin-4 based pathogenesis mechanisms and new therapies. Int J Biochem Cell Biol 2012;44:1519-30. https://doi.org/10.1016/j.biocel.2012.06.013
  94. Jensen CJ, Massie A, De Keyser J. Immune players in the CNS: the astrocyte. J Neuroimmune Pharmacol 2013;8:824-39. https://doi.org/10.1007/s11481-013-9480-6
  95. Saikali P, Cayrol R, Vincent T. Anti-aquaporin-4 auto-antibodies orchestrate the pathogenesis in neuromyelitis optica. Autoimmun Rev 2009;9:132-5. https://doi.org/10.1016/j.autrev.2009.04.004
  96. Pedersen SF, Stock C. Ion channels and transporters in cancer: pathophysiology, regulation, and clinical potential. Cancer Res 2013;73:1658-61. https://doi.org/10.1158/0008-5472.CAN-12-4188
  97. Morelli MB, Liberati S, Amantini C, Nabissi M, Santoni M, Farfariello V, et al. Expression and function of the transient receptor potential ion channel family in the hematologic malignancies. Curr Mol Pharmacol 2013, 2013 Jul 8 [Epub].
  98. Imbrici P, Camerino DC, Tricarico D. Major channels involved in neuropsychiatric disorders and therapeutic perspectives. Front Genet 2013;4:76.
  99. Skaper SD. Ion channels on microglia: therapeutic targets for neuroprotection. CNS Neurol Disord Drug Targets 2011;10:44-56. https://doi.org/10.2174/187152711794488638
  100. Bollimuntha S, Selvaraj S, Singh BB. Emerging roles of canonical TRP channels in neuronal function. Adv Exp Med Biol 2011;704:573-93. https://doi.org/10.1007/978-94-007-0265-3_31

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  9. ICEPO: the ion channel electrophysiology ontology vol.2016, pp.None, 2014, https://doi.org/10.1093/database/baw017
  10. Ion channelopathies in functional GI disorders vol.311, pp.4, 2016, https://doi.org/10.1152/ajpgi.00237.2016
  11. Teenage pregnancy with catecholaminergic polymorphic ventricular tachycardia and documented ICD discharges vol.4, pp.4, 2014, https://doi.org/10.1002/ccr3.366
  12. The multi-facet aspects of cell sentience and their relevance for the integrative brain actions: role of membrane protein energy landscape vol.27, pp.4, 2014, https://doi.org/10.1515/revneuro-2015-0049
  13. De Novo Heterogeneous Mutations in SCN2A and GRIN2A Genes and Seizures With Ictal Vocalizations vol.55, pp.9, 2016, https://doi.org/10.1177/0009922815601060
  14. Current Status of Pediatric Minimal Invasive Surgery (MIS) in Korea vol.19, pp.3, 2014, https://doi.org/10.7602/jmis.2016.19.3.84
  15. Structure-based assessment of disease-related mutations in human voltage-gated sodium channels vol.8, pp.6, 2017, https://doi.org/10.1007/s13238-017-0372-z
  16. ClC Channels and Transporters: Structure, Physiological Functions, and Implications in Human Chloride Channelopathies vol.8, pp.None, 2014, https://doi.org/10.3389/fphar.2017.00151
  17. Viral dependence on cellular ion channels - an emerging anti-viral target? vol.98, pp.3, 2017, https://doi.org/10.1099/jgv.0.000712
  18. Sodium Binding Sites and Permeation Mechanism in the NaChBac Channel: A Molecular Dynamics Study vol.13, pp.3, 2017, https://doi.org/10.1021/acs.jctc.6b01035
  19. µ-Conotoxins Modulating Sodium Currents in Pain Perception and Transmission: A Therapeutic Potential vol.15, pp.10, 2014, https://doi.org/10.3390/md15100295
  20. Sensing ion channel in neuron networks with graphene field effect transistors vol.5, pp.4, 2018, https://doi.org/10.1088/2053-1583/aad78f
  21. Association of epilepsy and asthma: a population-based retrospective cohort study vol.6, pp.None, 2014, https://doi.org/10.7717/peerj.4792
  22. Case 1: Term Infant with Intractable Seizures and Bilateral Hydronephrosis vol.19, pp.5, 2014, https://doi.org/10.1542/neo.19-5-e297
  23. egl-4 modulates electroconvulsive seizure duration in C. elegans vol.18, pp.2, 2014, https://doi.org/10.1007/s10158-018-0211-9
  24. Distinct epigenetic programs regulate cardiac myocyte development and disease in the human heart in vivo vol.9, pp.1, 2014, https://doi.org/10.1038/s41467-017-02762-z
  25. Identification of small-molecule ion channel modulators in C. elegans channelopathy models vol.9, pp.1, 2014, https://doi.org/10.1038/s41467-018-06514-5
  26. KCNMA1-linked channelopathy vol.151, pp.10, 2014, https://doi.org/10.1085/jgp.201912457
  27. Scorpion toxins targeting Kv1.3 channels: insights into immunosuppression vol.25, pp.n, 2014, https://doi.org/10.1590/1678-9199-jvatitd-1481-18
  28. Identification of putative pathogenic single nucleotide variants (SNVs) in genes associated with heart disease in 290 cases of stillbirth vol.14, pp.1, 2019, https://doi.org/10.1371/journal.pone.0210017
  29. 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
  30. Beyond the CRAC: Diversification of ion signaling in B cells vol.291, pp.1, 2019, https://doi.org/10.1111/imr.12770
  31. Considering smoking status, coexpression network analysis of non–small cell lung cancer at different cancer stages, exhibits important genes and pathways vol.120, pp.11, 2019, https://doi.org/10.1002/jcb.29246
  32. An integrative methodology based on protein-protein interaction networks for identification and functional annotation of disease-relevant genes applied to channelopathies vol.20, pp.1, 2014, https://doi.org/10.1186/s12859-019-3162-1
  33. Preventing Ethanol-Induced Brain and Eye Morphology Defects Using Optogenetics vol.1, pp.4, 2014, https://doi.org/10.1089/bioe.2019.0008
  34. Versatile symport transporters based on cyclic peptide dimers vol.56, pp.1, 2014, https://doi.org/10.1039/c9cc06644f
  35. Chronic inflammatory demyelinating polyradiculoneuropathy relapse after mexiletine withdrawal in a patient with concomitant myotonia congenita : A case report on a potential treatment option vol.99, pp.28, 2014, https://doi.org/10.1097/md.0000000000021117
  36. Comparative gain-of-function effects of the KCNMA1 -N999S mutation on human BK channel properties vol.123, pp.2, 2020, https://doi.org/10.1152/jn.00626.2019
  37. Migraine pathways and the identification of novel therapeutic targets vol.24, pp.3, 2014, https://doi.org/10.1080/14728222.2020.1728255
  38. Epilepsy and brain channelopathies from infancy to adulthood vol.41, pp.4, 2014, https://doi.org/10.1007/s10072-019-04190-x
  39. Contributions of natural products to ion channel pharmacology vol.37, pp.5, 2014, https://doi.org/10.1039/c9np00056a
  40. Quantum Electrochemical Equilibrium: Quantum Version of the Goldman-Hodgkin-Katz Equation vol.2, pp.2, 2014, https://doi.org/10.3390/quantum2020017
  41. Intertwined Detection and Recognition Roles of Tetrazine in Synergistic Anion‐π and H‐bond Based Anion Receptor vol.21, pp.12, 2014, https://doi.org/10.1002/cphc.202000289
  42. Ion channelopathies to bridge molecular lesions, channel function, and clinical therapies vol.472, pp.7, 2014, https://doi.org/10.1007/s00424-020-02424-y
  43. Neurobiological activity of conotoxins via sodium channel modulation vol.187, pp.None, 2020, https://doi.org/10.1016/j.toxicon.2020.08.019
  44. Functional evaluation of gene mutations in Long QT Syndrome: strength of evidence from in vitro assays for deciphering variants of uncertain significance vol.4, pp.1, 2020, https://doi.org/10.1186/s40949-020-00037-9
  45. Modulation of Adaptive Immunity and Viral Infections by Ion Channels vol.12, pp.None, 2021, https://doi.org/10.3389/fphys.2021.736681
  46. Structural Plasticity of the Selectivity Filter in Cation Channels vol.12, pp.None, 2021, https://doi.org/10.3389/fphys.2021.792958
  47. Functional Expression of TRPV1 Ion Channel in the Canine Peripheral Blood Mononuclear Cells vol.22, pp.6, 2021, https://doi.org/10.3390/ijms22063177
  48. Ginsenosides for cardiovascular diseases; update on pre-clinical and clinical evidence, pharmacological effects and the mechanisms of action vol.166, pp.None, 2021, https://doi.org/10.1016/j.phrs.2021.105481
  49. The function of SUMOylation and its crucial roles in the development of neurological diseases vol.35, pp.4, 2021, https://doi.org/10.1096/fj.202002702r
  50. Measurement of Melanin Metabolism in Live Cells by [U-13C]-L-Tyrosine Fate Tracing Using Liquid Chromatography-Mass Spectrometry vol.141, pp.7, 2014, https://doi.org/10.1016/j.jid.2021.01.007
  51. Delivery of trans-membrane proteins by liposomes; the effect of liposome size and formulation technique on the efficiency of protein delivery vol.606, pp.None, 2021, https://doi.org/10.1016/j.ijpharm.2021.120879
  52. Voltage-Gated Sodium Channels: A Prominent Target of Marine Toxins vol.19, pp.10, 2014, https://doi.org/10.3390/md19100562
  53. KCNG1-Related Syndromic Form of Congenital Neuromuscular Channelopathy in a Crossbred Calf vol.12, pp.11, 2021, https://doi.org/10.3390/genes12111792
  54. Deep-Sea Anemones Are Prospective Source of New Antimicrobial and Cytotoxic Compounds vol.19, pp.12, 2014, https://doi.org/10.3390/md19120654
  55. Advancing human disease research with fish evolutionary mutant models vol.38, pp.1, 2022, https://doi.org/10.1016/j.tig.2021.07.002