Abstract
Changes in blood and tissue pH accompany physiological and pathophysiological conditions including exercise, cardiac ischemia, ischemic stroke, and cocaine ingestion. These conditions are known to trigger the symptoms of electrical diseases in patients carrying sodium channel mutations. Protons cause a diverse set of changes to sodium channel gating, which generally lead to decreases in the amplitude of the transient sodium current and increases in the fraction of non-inactivating channels that pass persistent currents. These effects are shared with disease-causing mutants in neuronal, skeletal muscle, and cardiac tissue and may be compounded in mutants that impart greater proton sensitivity to sodium channels, suggesting a role of protons in triggering acute symptoms of electrical disease.
In this chapter, we review the mechanisms of proton block of the sodium channel pore and a suggested mode of action by which protons alter channel gating. We discuss the available data on isoform specificity of proton effects and tissue level effects. Finally, we review the role that protons play in disease and our own recent studies on proton-sensitizing mutants in cardiac and skeletal muscle sodium channels.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Allam S, Noble JS (2001) Cocaine-excited delirium and severe acidosis. Anaesthesia 56:385–386
Anselm DD, Evans JM, Baranchuk A (2014) Brugada phenocopy: a new electrocardiogram phenomenon. World J Cardiol 6:81–86. https://doi.org/10.4330/wjc.v6.i3.81
Antzelevitch C, Brugada P, Borggrefe M et al (2005) Brugada syndrome: report of the second consensus conference endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation 111:659–670. https://doi.org/10.1161/01.CIR.0000152479.54298.51
Baranchuk A, Nguyen T, Ryu MH et al (2012) Brugada phenocopy: new terminology and proposed classification. Ann Noninvasive Electrocardiol 17:299–314. https://doi.org/10.1111/j.1542-474X.2012.00525.x
Bennetts B, Parker MW, Cromer BA (2007) Inhibition of skeletal muscle ClC-1 chloride channels by low intracellular pH and ATP. J Biol Chem 282:32780–32791. https://doi.org/10.1074/jbc.M703259200
Butterworth J, Tennant MC (1989) Postmortem human brain pH and lactate in sudden infant death syndrome. J Neurochem 53:1494–1499. https://doi.org/10.1111/j.1471-4159.1989.tb08543.x
Campbell DT (1982) Do protons block Na+ channels by binding to a site outside the pore? Nature 298:165–167. https://doi.org/10.1038/298165a0
Cannon SC (1996) Sodium channel defects in myotonia and periodic paralysis. Annu Rev Neurosci 19:141–164. https://doi.org/10.1146/annurev.ne.19.030196.001041
Catterall WA (2012) Sodium channel mutations and epilepsy. In: Noebels JL, Avoli M, Rogawski MA et al (eds) Jasper’s basic mechanisms of the epilepsies, 4th edn. National Center for Biotechnology Information (US), Bethesda
Cheng X, Dib-Hajj SD, Tyrrell L et al (2010) Mutations at opposite ends of the DIII/S4-S5 linker of sodium channel Na V 1.7 produce distinct pain disorders. Mol Pain 6:24. https://doi.org/10.1186/1744-8069-6-24
Cheng J, Tester DJ, Tan B-H et al (2011) The common African American polymorphism SCN5A-S1103Y interacts with mutation SCN5A-R680H to increase late Na current. Physiol Genomics 43:461–466. https://doi.org/10.1152/physiolgenomics.00198.2010
Cobbe SM, Poole-Wilson PA (1980) The time of onset and severity of acidosis in myocardial ischaemia. J Mol Cell Cardiol 12:745–760
Constantinou JE, Gillis J, Ouvrier RA, Rahilly PM (1989) Hypoxic-ischaemic encephalopathy after near miss sudden infant death syndrome. Arch Dis Child 64:703–708. https://doi.org/10.1136/adc.64.5.703
DeCaen PG, Takahashi Y, Krulwich TA et al (2014) Ionic selectivity and thermal adaptations within the voltage-gated sodium channel family of alkaliphilic Bacillus. Elife 3:e04387. https://doi.org/10.7554/eLife.04387
Di Diego JM, Fish JM, Antzelevitch C (2005) Brugada syndrome and ischemia-induced ST-segment elevation. Similarities and differences. J Electrocardiol 38:14–17. https://doi.org/10.1016/j.jelectrocard.2005.06.003
Dravet C (2011) The core Dravet syndrome phenotype. Epilepsia 52:3–9. https://doi.org/10.1111/j.1528-1167.2011.02994.x
Epstein SK, Singh N (2001) Respiratory acidosis. Respir Care 46:366–383
Estacion M, Gasser A, Dib-Hajj SD, Waxman SG (2010) A sodium channel mutation linked to epilepsy increases ramp and persistent current of Nav1.3 and induces hyperexcitability in hippocampal neurons. Exp Neurol 224:362–368. https://doi.org/10.1016/j.expneurol.2010.04.012
Fleet WF, Johnson TA, Graebner CA, Gettes LS (1985) Effect of serial brief ischemic episodes on extracellular K+, pH, and activation in the pig. Circulation 72:922–932. https://doi.org/10.1161/01.CIR.72.4.922
Fry CH, Poole-Wilson PA (1981) Effects of acid-base changes on excitation--contraction coupling in guinea-pig and rabbit cardiac ventricular muscle. J Physiol 313:141–160
García-Borbolla M, García-Borbolla R, Valenzuela LF et al (2007) Ventricular tachycardia induced by exercise testing in a patient with Brugada syndrome. Rev Esp Cardiol 60:993–994
Ghovanloo M-R, Abdelsayed M, Peters CH, Ruben PC (2017) A mixed periodic paralysis & myotonia mutant, P1158S, imparts pH sensitivity in skeletal muscle voltage-gated sodium channels. bioRxiv 164988. https://doi.org/10.1101/164988
Haberlandt E, Canestrini C, Brunner-Krainz M et al (2009) Epilepsy in patients with propionic acidemia. Neuropediatrics 40:120–125. https://doi.org/10.1055/s-0029-1243167
Hermansen L, Osnes JB (1972) Blood and muscle pH after maximal exercise in man. J Appl Physiol 32:304–308
Heron SE, Crossland KM, Andermann E et al (2002) Sodium-channel defects in benign familial neonatal-infantile seizures. Lancet 360:851–852. https://doi.org/10.1016/S0140-6736(02)09968-3
Hick JL, Smith SW, Lynch MT (1999) Metabolic acidosis in restraint-associated cardiac arrest: a case series. Acad Emerg Med 6:239–243
Hu R-M, Tan B-H, Tester DJ et al (2015) Arrhythmogenic biophysical phenotype for SCN5A mutation S1787N depends upon splice variant background and intracellular acidosis. PLoS One 10:e0124921. https://doi.org/10.1371/journal.pone.0124921
Huang L, Zhao S, Lu W et al (2015) Acidosis-induced dysfunction of cortical GABAergic neurons through astrocyte-related excitotoxicity. PLoS One 10:e0140324. https://doi.org/10.1371/journal.pone.0140324
Jones DK, Peters CH, Tolhurst SA et al (2011) Extracellular proton modulation of the cardiac voltage-gated sodium channel, Nav1.5. Biophys J 101:2147–2156. https://doi.org/10.1016/j.bpj.2011.08.056
Jones DK, Claydon TW, Ruben PC (2013a) Extracellular protons inhibit charge immobilization in the cardiac voltage-gated sodium channel. Biophys J 105:101–107. https://doi.org/10.1016/j.bpj.2013.04.022
Jones DK, Peters CH, Allard CR et al (2013b) Proton sensors in the pore domain of the cardiac voltage-gated sodium channel. J Biol Chem 288:4782–4791. https://doi.org/10.1074/jbc.M112.434266
Kang I-S, Cho J-H, Choi I-S et al (2016) Acidic pH modulation of Na+ channels in trigeminal mesencephalic nucleus neurons. Neuroreport 27:1274–1280. https://doi.org/10.1097/WNR.0000000000000692
Khan A, Romantseva L, Lam A et al (2002) Role of outer ring carboxylates of the rat skeletal muscle sodium channel pore in proton block. J Physiol 543:71–84. https://doi.org/10.1113/jphysiol.2002.021014
Khan A, Kyle JW, Hanck DA et al (2006) Isoform-dependent interaction of voltage-gated sodium channels with protons. J Physiol 576:493–501. https://doi.org/10.1113/jphysiol.2006.115659
Kiyosue T, Arita M (1989) Late sodium current and its contribution to action potential configuration in guinea pig ventricular myocytes. Circ Res 64:389–397. https://doi.org/10.1161/01.RES.64.2.389
Kléber AG, Janse MJ, Wilms-Schopmann FJ et al (1986) Changes in conduction velocity during acute ischemia in ventricular myocardium of the isolated porcine heart. Circulation 73:189–198. https://doi.org/10.1161/01.CIR.73.1.189
Komukai K, Brette F, Pascarel C, Orchard CH (2002) Electrophysiological response of rat ventricular myocytes to acidosis. Am J Physiol Heart Circ Physiol 283:H412–H422. https://doi.org/10.1152/ajpheart.01042.2001
Li F, Liu X, Su Z, Sun R (2011) Acidosis leads to brain dysfunctions through impairing cortical GABAergic neurons. Biochem Biophys Res Commun 410:775–779. https://doi.org/10.1016/j.bbrc.2011.06.053
Littmann L, Monroe MH, Svenson RH (2000) Brugada-type electrocardiographic pattern induced by cocaine. Mayo Clin Proc 75:845–849. https://doi.org/10.4065/75.8.845
Ma X, Zhang Y, Yang Y et al (2011) Epilepsy in children with methylmalonic acidemia: electroclinical features and prognosis. Brain and Development 33:790–795. https://doi.org/10.1016/j.braindev.2011.06.001
Makita N, Behr E, Shimizu W et al (2008) The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome. J Clin Invest 118:2219–2229. https://doi.org/10.1172/JCI34057
McClelland VM, Bakalinova DB, Hendriksz C, Singh RP (2009) Glutaric aciduria type 1 presenting with epilepsy. Dev Med Child Neurol 51:235–239. https://doi.org/10.1111/j.1469-8749.2008.03240.x
Meadows LS, Isom LL (2005) Sodium channels as macromolecular complexes: implications for inherited arrhythmia syndromes. Cardiovasc Res 67:448–458. https://doi.org/10.1016/j.cardiores.2005.04.003
Miller TM, Dias da Silva MR, Miller HA et al (2004) Correlating phenotype and genotype in the periodic paralyses. Neurology 63:1647–1655
Murphy L, Renodin D, Antzelevitch C et al (2011) Extracellular proton depression of peak and late Na+ current in the canine left ventricle. Am J Physiol Heart Circ Physiol 301:H936–H944. https://doi.org/10.1152/ajpheart.00204.2011
Ortega-Carnicer J, Bertos-Polo J, Gutiérrez-Tirado C (2001) Aborted sudden death, transient Brugada pattern, and wide QRS dysrrhythmias after massive cocaine ingestion. J Electrocardiol 34:345–349
Payandeh J, Scheuer T, Zheng N, Catterall WA (2011) The crystal structure of a voltage-gated sodium channel. Nature 475:353–358. https://doi.org/10.1038/nature10238
Payandeh J, Gamal El-Din TM, Scheuer T et al (2012) Crystal structure of a voltage-gated sodium channel in two potentially inactivated states. Nature 486:135–139. https://doi.org/10.1038/nature11077
Pedersen TH, de Paoli F, Nielsen OB (2005) Increased excitability of acidified skeletal muscle. J Gen Physiol 125:237–246. https://doi.org/10.1085/jgp.200409173
Peters C, Sokolov S, Rajamani S, Ruben P (2013) Effects of the antianginal drug, ranolazine, on the brain sodium channel NaV1.2 and its modulation by extracellular protons. Br J Pharmacol 169:704–716. https://doi.org/10.1111/bph.12150
Peters CH, Abdelsayed M, Ruben PC (2016) Triggers for arrhythmogenesis in the Brugada and long QT 3 syndromes. Prog Biophys Mol Biol 120(1–3):77–88. https://doi.org/10.1016/j.pbiomolbio.2015.12.009
Postema PG, Vlaar APJ, DeVries JH, Tan HL (2011) Familial Brugada syndrome uncovered by hyperkalaemic diabetic ketoacidosis. Europace 13:1509–1510. https://doi.org/10.1093/europace/eur151
Ruan Y, Denegri M, Liu N et al (2010) Trafficking defects and gating abnormalities of a novel SCN5A mutation question gene-specific therapy in long QT syndrome type 3. Circ Res 106:1374–1383. https://doi.org/10.1161/CIRCRESAHA.110.218891
Scalmani P, Rusconi R, Armatura E et al (2006) Effects in neocortical neurons of mutations of the Na(v)1.2 Na+ channel causing benign familial neonatal-infantile seizures. J Neurosci 26:10100–10109. https://doi.org/10.1523/JNEUROSCI.2476-06.2006
Shi YP, Cheng YM, Van Slyke AC, Claydon TW (2014) External protons destabilize the activated voltage sensor in hERG channels. Eur Biophys J 43:59–69. https://doi.org/10.1007/s00249-013-0940-y
Shimizu W, Antzelevitch C (1999) Cellular basis for long QT, transmural dispersion of repolarization, and torsade de pointes in the long QT syndrome. J Electrocardiol 32(Suppl):177–184
Silva JR, Goldstein SAN (2013a) Voltage-sensor movements describe slow inactivation of voltage-gated sodium channels I: wild-type skeletal muscle Na(V)1.4. J Gen Physiol 141:309–321. https://doi.org/10.1085/jgp.201210909
Silva JR, Goldstein SAN (2013b) Voltage-sensor movements describe slow inactivation of voltage-gated sodium channels II: a periodic paralysis mutation in Na(V)1.4 (L689I). J Gen Physiol 141:323–334. https://doi.org/10.1085/jgp.201210910
Sokolov S, Peters CH, Rajamani S, Ruben PC (2013) Proton-dependent inhibition of the cardiac sodium channel Nav1.5 by ranolazine. Front Pharmacol 4. https://doi.org/10.3389/fphar.2013.00078
Sun YM, Favre I, Schild L, Moczydlowski E (1997) On the structural basis for size-selective permeation of organic cations through the voltage-gated sodium channel. Effect of alanine mutations at the DEKA locus on selectivity, inhibition by Ca2+ and H+, and molecular sieving. J Gen Physiol 110:693–715
Tang Q, Ma J, Zhang P et al (2012) Persistent sodium current and Na+/H+ exchange contributes to the augmentation of the reverse Na+/Ca2+ exchange during hypoxia or acute ischemia in ventricular myocytes. Pflügers Arch - Eur J Physiol 463:513–522. https://doi.org/10.1007/s00424-011-1070-y
Terlau H, Heinemann SH, Stühmer W et al (1991) Mapping the site of block by tetrodotoxin and saxitoxin of sodium channel II. FEBS Lett 293:93–96. https://doi.org/10.1016/0014-5793(91)81159-6
Tombaugh GC, Somjen GG (1996) Effects of extracellular pH on voltage-gated Na+, K+ and Ca2+ currents in isolated rat CA1 neurons. J Physiol 493:719–732
Van Slyke AC, Cheng YM, Mafi P et al (2012) Proton block of the pore underlies the inhibition of hERG cardiac K+ channels during acidosis. Am J Physiol Cell Physiol 302:C1797–C1806. https://doi.org/10.1152/ajpcell.00324.2011
Veeramah KR, O’Brien JE, Meisler MH et al (2012) De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. Am J Hum Genet 90:502–510. https://doi.org/10.1016/j.ajhg.2012.01.006
Vilin YY, Fujimoto E, Ruben PC (2001) A single residue differentiates between human cardiac and skeletal muscle Na+ channel slow inactivation. Biophys J 80:2221–2230. https://doi.org/10.1016/S0006-3495(01)76195-4
Vilin YY, Peters CH, Ruben PC (2012) Acidosis differentially modulates inactivation in na(v)1.2, na(v)1.4, and na(v)1.5 channels. Front Pharmacol 3:109. https://doi.org/10.3389/fphar.2012.00109
Wang Q, Shen J, Splawski I et al (1995) SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 80:805–811
Wang W, Tiwari JK, Bradley SR et al (2001) Acidosis-stimulated neurons of the medullary raphe are serotonergic. J Neurophysiol 85:2224–2235
Watson CL, Gold MR (1995) Effect of intracellular and extracellular acidosis on sodium current in ventricular myocytes. Am J Phys 268:H1749–H1756
Webb J, Cannon SC (2008) Cold-induced defects of sodium channel gating in atypical periodic paralysis plus myotonia. Neurology 70:755–761. https://doi.org/10.1212/01.wnl.0000265397.70057.d8
Wilde AAM, Postema PG, Di Diego JM et al (2010) The pathophysiological mechanism underlying Brugada syndrome. J Mol Cell Cardiol 49:543–553. https://doi.org/10.1016/j.yjmcc.2010.07.012
Woodhull AM (1973) Ionic blockage of sodium channels in nerve. J Gen Physiol 61:687–708
Yan GX, Kléber AG (1992) Changes in extracellular and intracellular pH in ischemic rabbit papillary muscle. Circ Res 71:460–470
Yatani A, Brown AM, Akaike N (1984) Effect of extracellular pH on sodium current in isolated, single rat ventricular cells. J Membr Biol 78:163–168
Yu FH, Mantegazza M, Westenbroek RE et al (2006) Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nat Neurosci 9:1142–1149. https://doi.org/10.1038/nn1754
Zhan R-Z, Nadler JV, Schwartz-Bloom RD (2007) Impaired firing and sodium channel function in CA1 hippocampal interneurons after transient cerebral ischemia. J Cereb Blood Flow Metab 27:1444–1452. https://doi.org/10.1038/sj.jcbfm.9600448
Zhang JF, Siegelbaum SA (1991) Effects of external protons on single cardiac sodium channels from guinea pig ventricular myocytes. J Gen Physiol 98:1065–1083
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG
About this chapter
Cite this chapter
Peters, C.H., Ghovanloo, MR., Gershome, C., Ruben, P.C. (2018). pH Modulation of Voltage-Gated Sodium Channels. In: Chahine, M. (eds) Voltage-gated Sodium Channels: Structure, Function and Channelopathies. Handbook of Experimental Pharmacology, vol 246. Springer, Cham. https://doi.org/10.1007/164_2018_99
Download citation
DOI: https://doi.org/10.1007/164_2018_99
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-90283-8
Online ISBN: 978-3-319-90284-5
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)