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Pathway Description
Quinidine Action Pathway
Homo sapiens
Drug Action Pathway
Created: 2013-08-22
Last Updated: 2025-01-29
This pathway illustrates the quinidine targets involved in antiarrhythmic therapy. Contractile activity of cardiac myocytes is elicited via action potentials mediated by a number of ion channel proteins. During rest, or diastole, cells maintain a negative membrane potential; i.e. the inside the cell is negatively charged relative to the cells’ extracellular environment. Membrane ion pumps, such as the sodium-potassium ATPase and sodium-calcium exchanger (NCX), maintain low intracellular sodium (5 mM) and calcium (100 nM) concentrations and high intracellular potassium (140 mM) concentrations. Conversely, extracellular concentrations of sodium (140 mM) and calcium (1.8 mM) are relatively high and extracellular potassium concentrations are low (5 mM). At rest, the cardiac cell membrane is impermeable to sodium and calcium ions, but is permeable to potassium ions via inward rectifier potassium channels (I-K1), which allow an outward flow of potassium ions down their concentration gradient. The positive outflow of potassium ions aids in maintaining the negative intracellular electric potential. When cells reach a critical threshold potential, voltage-gated sodium channels (I-Na) open and the rapid influx of positive sodium ions into the cell occurs as the ions travel down their electrochemical gradient. This is known as the rapid depolarization or upstroke phase of the cardiac action potential. Sodium channels then close and rapidly activated potassium channels such as the voltage-gated transient outward delayed rectifying potassium channel (I-Kto) and the voltage-gated ultra rapid delayed rectifying potassium channel (I-Kur) open. These events make up the early repolarization phase during which potassium ions flow out of the cell and sodium ions are continually pumped out. During the next phase, known as the plateau phase, calcium L-type channels (I-CaL) open and the resulting influx of calcium ions roughly balances the outward flow of potassium channels. During the final repolarization phase, the voltage-gated rapid (I-Kr) and slow (I-Ks) delayed rectifying potassium channels open increasing the outflow of potassium ions and repolarizing the cell. The extra sodium and calcium ions that entered the cell during the action potential are extruded via sodium-potassium ATPases and NCX and intra- and extracellular ion concentrations are restored. In specialized pacemaker cells, gradual depolarization to threshold occurs via funny channels (I-f).
Quinidine, a diastereomer of quinine, is a Class 1A antiarrhythmic drug that is isolated from the bark of the Cinchona plant or other related species. This alkaloid dampens the excitability of cardiac and skeletal muscles by blocking sodium and potassium currents across cellular membranes. At low concentrations, it blocks the voltage-gated sodium (I-Na) and rapid delayed rectifying potassium (I-Kr) channels. I-Na is responsible for the rapid upstroke in cell membrane potential observed on the cardiac myocyte action potential. I-Kr is partially responsible for the final repolarization phase of the action potential. By blocking I-Na, quinidine increases the threshold of excitability and decreases automaticity. I-Kr block results in action potential prolongation. At higher concentrations, quinidine also blocks voltage-gated delayed rectifying potassium channel (I-Ks), inward rectifier potassium channel (I-K1), voltage-gated transient outward delayed rectifying potassium channel (I-Kto), and L-type calcium channels (I-CaL). Quinidine also exerts antimuscarinic effects, which increase AV nodal conduction and antagonize alpha-adrenergic effects. Quinidine may be used to maintain sinus rhythm in atrial fibrillation or flutter and prevent recurrence of ventricular fibrillation or tachycardia. The side effects of quinidine include diarrhea and on rare occasions (2-8%) Torsades de Pointes.
References
Quinidine Pathway References
Dhein, S. Antiarrhythmic drugs. In S. Offermanns, & W. Rosenthal (Eds.). Encyclopedic reference of molecular pharmacology. (2004) p.49-51. Berlin, Germany: Springer.
Nattel S, Carlsson L: Innovative approaches to anti-arrhythmic drug therapy. Nat Rev Drug Discov. 2006 Dec;5(12):1034-49. doi: 10.1038/nrd2112.
Pubmed: 17139288
Giudicessi JR, Ye D, Tester DJ, Crotti L, Mugione A, Nesterenko VV, Albertson RM, Antzelevitch C, Schwartz PJ, Ackerman MJ: Transient outward current (I(to)) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome. Heart Rhythm. 2011 Jul;8(7):1024-32. doi: 10.1016/j.hrthm.2011.02.021. Epub 2011 Feb 22.
Pubmed: 21349352
Lee YC, Durr A, Majczenko K, Huang YH, Liu YC, Lien CC, Tsai PC, Ichikawa Y, Goto J, Monin ML, Li JZ, Chung MY, Mundwiller E, Shakkottai V, Liu TT, Tesson C, Lu YC, Brice A, Tsuji S, Burmeister M, Stevanin G, Soong BW: Mutations in KCND3 cause spinocerebellar ataxia type 22. Ann Neurol. 2012 Dec;72(6):859-69. doi: 10.1002/ana.23701.
Pubmed: 23280837
Kurihara M, Ishiura H, Sasaki T, Otsuka J, Hayashi T, Terao Y, Matsukawa T, Mitsui J, Kaneko J, Nishiyama K, Doi K, Yoshimura J, Morishita S, Shimizu J, Tsuji S: Novel De Novo KCND3 Mutation in a Japanese Patient with Intellectual Disability, Cerebellar Ataxia, Myoclonus, and Dystonia. Cerebellum. 2018 Apr;17(2):237-242. doi: 10.1007/s12311-017-0883-4.
Pubmed: 28895081
Bahring R, Dannenberg J, Peters HC, Leicher T, Pongs O, Isbrandt D: Conserved Kv4 N-terminal domain critical for effects of Kv channel-interacting protein 2.2 on channel expression and gating. J Biol Chem. 2001 Jun 29;276(26):23888-94. doi: 10.1074/jbc.M101320200. Epub 2001 Apr 3.
Pubmed: 11287421
An WF, Bowlby MR, Betty M, Cao J, Ling HP, Mendoza G, Hinson JW, Mattsson KI, Strassle BW, Trimmer JS, Rhodes KJ: Modulation of A-type potassium channels by a family of calcium sensors. Nature. 2000 Feb 3;403(6769):553-6. doi: 10.1038/35000592.
Pubmed: 10676964
Ohya S, Morohashi Y, Muraki K, Tomita T, Watanabe M, Iwatsubo T, Imaizumi Y: Molecular cloning and expression of the novel splice variants of K(+) channel-interacting protein 2. Biochem Biophys Res Commun. 2001 Mar 23;282(1):96-102. doi: 10.1006/bbrc.2001.4558.
Pubmed: 11263977
Schmitt N, Schwarz M, Peretz A, Abitbol I, Attali B, Pongs O: A recessive C-terminal Jervell and Lange-Nielsen mutation of the KCNQ1 channel impairs subunit assembly. EMBO J. 2000 Feb 1;19(3):332-40. doi: 10.1093/emboj/19.3.332.
Pubmed: 10654932
Selyanko AA, Hadley JK, Wood IC, Abogadie FC, Jentsch TJ, Brown DA: Inhibition of KCNQ1-4 potassium channels expressed in mammalian cells via M1 muscarinic acetylcholine receptors. J Physiol. 2000 Feb 1;522 Pt 3:349-55. doi: 10.1111/j.1469-7793.2000.t01-2-00349.x.
Pubmed: 10713961
Angelo K, Jespersen T, Grunnet M, Nielsen MS, Klaerke DA, Olesen SP: KCNE5 induces time- and voltage-dependent modulation of the KCNQ1 current. Biophys J. 2002 Oct;83(4):1997-2006. doi: 10.1016/S0006-3495(02)73961-1.
Pubmed: 12324418
Kang C, Tian C, Sonnichsen FD, Smith JA, Meiler J, George AL Jr, Vanoye CG, Kim HJ, Sanders CR: Structure of KCNE1 and implications for how it modulates the KCNQ1 potassium channel. Biochemistry. 2008 Aug 5;47(31):7999-8006. doi: 10.1021/bi800875q. Epub 2008 Jul 9.
Pubmed: 18611041
Tesson F, Donger C, Denjoy I, Berthet M, Bennaceur M, Petit C, Coumel P, Schwarts K, Guicheney P: Exclusion of KCNE1 (IsK) as a candidate gene for Jervell and Lange-Nielsen syndrome. J Mol Cell Cardiol. 1996 Sep;28(9):2051-5.
Pubmed: 8899564
Schulze-Bahr E, Wang Q, Wedekind H, Haverkamp W, Chen Q, Sun Y, Rubie C, Hordt M, Towbin JA, Borggrefe M, Assmann G, Qu X, Somberg JC, Breithardt G, Oberti C, Funke H: KCNE1 mutations cause jervell and Lange-Nielsen syndrome. Nat Genet. 1997 Nov;17(3):267-8. doi: 10.1038/ng1197-267.
Pubmed: 9354783
Andelfinger G, Tapper AR, Welch RC, Vanoye CG, George AL Jr, Benson DW: KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes. Am J Hum Genet. 2002 Sep;71(3):663-8. doi: 10.1086/342360. Epub 2002 Jul 29.
Pubmed: 12148092
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: Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J Clin Invest. 2002 Aug;110(3):381-8. doi: 10.1172/JCI15183.
Pubmed: 12163457
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: A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res. 2005 Apr 15;96(7):800-7. doi: 10.1161/01.RES.0000162101.76263.8c. Epub 2005 Mar 10.
Pubmed: 15761194
Perier F, Radeke CM, Vandenberg CA: Primary structure and characterization of a small-conductance inwardly rectifying potassium channel from human hippocampus. Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):6240-4. doi: 10.1073/pnas.91.13.6240.
Pubmed: 8016146
Tang W, Yang XC: Cloning a novel human brain inward rectifier potassium channel and its functional expression in Xenopus oocytes. FEBS Lett. 1994 Jul 18;348(3):239-43. doi: 10.1016/0014-5793(94)00612-1.
Pubmed: 8034048
Makhina EN, Kelly AJ, Lopatin AN, Mercer RW, Nichols CG: Cloning and expression of a novel human brain inward rectifier potassium channel. J Biol Chem. 1994 Aug 12;269(32):20468-74.
Pubmed: 8051145
Soldatov NM: Molecular diversity of L-type Ca2+ channel transcripts in human fibroblasts. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4628-32. doi: 10.1073/pnas.89.10.4628.
Pubmed: 1316612
Schultz D, Mikala G, Yatani A, Engle DB, Iles DE, Segers B, Sinke RJ, Weghuis DO, Klockner U, Wakamori M, et al.: Cloning, chromosomal localization, and functional expression of the alpha 1 subunit of the L-type voltage-dependent calcium channel from normal human heart. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6228-32. doi: 10.1073/pnas.90.13.6228.
Pubmed: 8392192
Soldatov NM: Genomic structure of human L-type Ca2+ channel. Genomics. 1994 Jul 1;22(1):77-87. doi: 10.1006/geno.1994.1347.
Pubmed: 7959794
Klugbauer N, Lacinova L, Marais E, Hobom M, Hofmann F: Molecular diversity of the calcium channel alpha2delta subunit. J Neurosci. 1999 Jan 15;19(2):684-91.
Pubmed: 9880589
Gao B, Sekido Y, Maximov A, Saad M, Forgacs E, Latif F, Wei MH, Lerman M, Lee JH, Perez-Reyes E, Bezprozvanny I, Minna JD: Functional properties of a new voltage-dependent calcium channel alpha(2)delta auxiliary subunit gene (CACNA2D2). J Biol Chem. 2000 Apr 21;275(16):12237-42. doi: 10.1074/jbc.275.16.12237.
Pubmed: 10766861
Hobom M, Dai S, Marais E, Lacinova L, Hofmann F, Klugbauer N: Neuronal distribution and functional characterization of the calcium channel alpha2delta-2 subunit. Eur J Neurosci. 2000 Apr;12(4):1217-26. doi: 10.1046/j.1460-9568.2000.01009.x.
Pubmed: 10762351
Powers PA, Liu S, Hogan K, Gregg RG: Skeletal muscle and brain isoforms of a beta-subunit of human voltage-dependent calcium channels are encoded by a single gene. J Biol Chem. 1992 Nov 15;267(32):22967-72.
Pubmed: 1385409
Williams ME, Feldman DH, McCue AF, Brenner R, Velicelebi G, Ellis SB, Harpold MM: Structure and functional expression of alpha 1, alpha 2, and beta subunits of a novel human neuronal calcium channel subtype. Neuron. 1992 Jan;8(1):71-84. doi: 10.1016/0896-6273(92)90109-q.
Pubmed: 1309651
Collin T, Wang JJ, Nargeot J, Schwartz A: Molecular cloning of three isoforms of the L-type voltage-dependent calcium channel beta subunit from normal human heart. Circ Res. 1993 Jun;72(6):1337-44. doi: 10.1161/01.res.72.6.1337.
Pubmed: 7916667
Striated Muscle Contraction References
Cooke R: The sliding filament model: 1972-2004. J Gen Physiol. 2004 Jun;123(6):643-56. doi: 10.1085/jgp.200409089.
Pubmed: 15173218
Szent-Gyorgyi A: The mechanism of muscle contraction. Proc Natl Acad Sci U S A. 1974 Sep;71(9):3343-4.
Pubmed: 4610574
Kuo IY, Ehrlich BE: Signaling in muscle contraction. Cold Spring Harb Perspect Biol. 2015 Feb 2;7(2):a006023. doi: 10.1101/cshperspect.a006023.
Pubmed: 25646377
Giudicessi JR, Ye D, Tester DJ, Crotti L, Mugione A, Nesterenko VV, Albertson RM, Antzelevitch C, Schwartz PJ, Ackerman MJ: Transient outward current (I(to)) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome. Heart Rhythm. 2011 Jul;8(7):1024-32. doi: 10.1016/j.hrthm.2011.02.021. Epub 2011 Feb 22.
Pubmed: 21349352
Lee YC, Durr A, Majczenko K, Huang YH, Liu YC, Lien CC, Tsai PC, Ichikawa Y, Goto J, Monin ML, Li JZ, Chung MY, Mundwiller E, Shakkottai V, Liu TT, Tesson C, Lu YC, Brice A, Tsuji S, Burmeister M, Stevanin G, Soong BW: Mutations in KCND3 cause spinocerebellar ataxia type 22. Ann Neurol. 2012 Dec;72(6):859-69. doi: 10.1002/ana.23701.
Pubmed: 23280837
Kurihara M, Ishiura H, Sasaki T, Otsuka J, Hayashi T, Terao Y, Matsukawa T, Mitsui J, Kaneko J, Nishiyama K, Doi K, Yoshimura J, Morishita S, Shimizu J, Tsuji S: Novel De Novo KCND3 Mutation in a Japanese Patient with Intellectual Disability, Cerebellar Ataxia, Myoclonus, and Dystonia. Cerebellum. 2018 Apr;17(2):237-242. doi: 10.1007/s12311-017-0883-4.
Pubmed: 28895081
Bahring R, Dannenberg J, Peters HC, Leicher T, Pongs O, Isbrandt D: Conserved Kv4 N-terminal domain critical for effects of Kv channel-interacting protein 2.2 on channel expression and gating. J Biol Chem. 2001 Jun 29;276(26):23888-94. doi: 10.1074/jbc.M101320200. Epub 2001 Apr 3.
Pubmed: 11287421
An WF, Bowlby MR, Betty M, Cao J, Ling HP, Mendoza G, Hinson JW, Mattsson KI, Strassle BW, Trimmer JS, Rhodes KJ: Modulation of A-type potassium channels by a family of calcium sensors. Nature. 2000 Feb 3;403(6769):553-6. doi: 10.1038/35000592.
Pubmed: 10676964
Ohya S, Morohashi Y, Muraki K, Tomita T, Watanabe M, Iwatsubo T, Imaizumi Y: Molecular cloning and expression of the novel splice variants of K(+) channel-interacting protein 2. Biochem Biophys Res Commun. 2001 Mar 23;282(1):96-102. doi: 10.1006/bbrc.2001.4558.
Pubmed: 11263977
Schmitt N, Schwarz M, Peretz A, Abitbol I, Attali B, Pongs O: A recessive C-terminal Jervell and Lange-Nielsen mutation of the KCNQ1 channel impairs subunit assembly. EMBO J. 2000 Feb 1;19(3):332-40. doi: 10.1093/emboj/19.3.332.
Pubmed: 10654932
Selyanko AA, Hadley JK, Wood IC, Abogadie FC, Jentsch TJ, Brown DA: Inhibition of KCNQ1-4 potassium channels expressed in mammalian cells via M1 muscarinic acetylcholine receptors. J Physiol. 2000 Feb 1;522 Pt 3:349-55. doi: 10.1111/j.1469-7793.2000.t01-2-00349.x.
Pubmed: 10713961
Angelo K, Jespersen T, Grunnet M, Nielsen MS, Klaerke DA, Olesen SP: KCNE5 induces time- and voltage-dependent modulation of the KCNQ1 current. Biophys J. 2002 Oct;83(4):1997-2006. doi: 10.1016/S0006-3495(02)73961-1.
Pubmed: 12324418
Kang C, Tian C, Sonnichsen FD, Smith JA, Meiler J, George AL Jr, Vanoye CG, Kim HJ, Sanders CR: Structure of KCNE1 and implications for how it modulates the KCNQ1 potassium channel. Biochemistry. 2008 Aug 5;47(31):7999-8006. doi: 10.1021/bi800875q. Epub 2008 Jul 9.
Pubmed: 18611041
Tesson F, Donger C, Denjoy I, Berthet M, Bennaceur M, Petit C, Coumel P, Schwarts K, Guicheney P: Exclusion of KCNE1 (IsK) as a candidate gene for Jervell and Lange-Nielsen syndrome. J Mol Cell Cardiol. 1996 Sep;28(9):2051-5.
Pubmed: 8899564
Schulze-Bahr E, Wang Q, Wedekind H, Haverkamp W, Chen Q, Sun Y, Rubie C, Hordt M, Towbin JA, Borggrefe M, Assmann G, Qu X, Somberg JC, Breithardt G, Oberti C, Funke H: KCNE1 mutations cause jervell and Lange-Nielsen syndrome. Nat Genet. 1997 Nov;17(3):267-8. doi: 10.1038/ng1197-267.
Pubmed: 9354783
Andelfinger G, Tapper AR, Welch RC, Vanoye CG, George AL Jr, Benson DW: KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes. Am J Hum Genet. 2002 Sep;71(3):663-8. doi: 10.1086/342360. Epub 2002 Jul 29.
Pubmed: 12148092
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: Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J Clin Invest. 2002 Aug;110(3):381-8. doi: 10.1172/JCI15183.
Pubmed: 12163457
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: A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res. 2005 Apr 15;96(7):800-7. doi: 10.1161/01.RES.0000162101.76263.8c. Epub 2005 Mar 10.
Pubmed: 15761194
Perier F, Radeke CM, Vandenberg CA: Primary structure and characterization of a small-conductance inwardly rectifying potassium channel from human hippocampus. Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):6240-4. doi: 10.1073/pnas.91.13.6240.
Pubmed: 8016146
Tang W, Yang XC: Cloning a novel human brain inward rectifier potassium channel and its functional expression in Xenopus oocytes. FEBS Lett. 1994 Jul 18;348(3):239-43. doi: 10.1016/0014-5793(94)00612-1.
Pubmed: 8034048
Makhina EN, Kelly AJ, Lopatin AN, Mercer RW, Nichols CG: Cloning and expression of a novel human brain inward rectifier potassium channel. J Biol Chem. 1994 Aug 12;269(32):20468-74.
Pubmed: 8051145
Soldatov NM: Molecular diversity of L-type Ca2+ channel transcripts in human fibroblasts. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4628-32. doi: 10.1073/pnas.89.10.4628.
Pubmed: 1316612
Schultz D, Mikala G, Yatani A, Engle DB, Iles DE, Segers B, Sinke RJ, Weghuis DO, Klockner U, Wakamori M, et al.: Cloning, chromosomal localization, and functional expression of the alpha 1 subunit of the L-type voltage-dependent calcium channel from normal human heart. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6228-32. doi: 10.1073/pnas.90.13.6228.
Pubmed: 8392192
Soldatov NM: Genomic structure of human L-type Ca2+ channel. Genomics. 1994 Jul 1;22(1):77-87. doi: 10.1006/geno.1994.1347.
Pubmed: 7959794
Klugbauer N, Lacinova L, Marais E, Hobom M, Hofmann F: Molecular diversity of the calcium channel alpha2delta subunit. J Neurosci. 1999 Jan 15;19(2):684-91.
Pubmed: 9880589
Gao B, Sekido Y, Maximov A, Saad M, Forgacs E, Latif F, Wei MH, Lerman M, Lee JH, Perez-Reyes E, Bezprozvanny I, Minna JD: Functional properties of a new voltage-dependent calcium channel alpha(2)delta auxiliary subunit gene (CACNA2D2). J Biol Chem. 2000 Apr 21;275(16):12237-42. doi: 10.1074/jbc.275.16.12237.
Pubmed: 10766861
Hobom M, Dai S, Marais E, Lacinova L, Hofmann F, Klugbauer N: Neuronal distribution and functional characterization of the calcium channel alpha2delta-2 subunit. Eur J Neurosci. 2000 Apr;12(4):1217-26. doi: 10.1046/j.1460-9568.2000.01009.x.
Pubmed: 10762351
Powers PA, Liu S, Hogan K, Gregg RG: Skeletal muscle and brain isoforms of a beta-subunit of human voltage-dependent calcium channels are encoded by a single gene. J Biol Chem. 1992 Nov 15;267(32):22967-72.
Pubmed: 1385409
Williams ME, Feldman DH, McCue AF, Brenner R, Velicelebi G, Ellis SB, Harpold MM: Structure and functional expression of alpha 1, alpha 2, and beta subunits of a novel human neuronal calcium channel subtype. Neuron. 1992 Jan;8(1):71-84. doi: 10.1016/0896-6273(92)90109-q.
Pubmed: 1309651
Collin T, Wang JJ, Nargeot J, Schwartz A: Molecular cloning of three isoforms of the L-type voltage-dependent calcium channel beta subunit from normal human heart. Circ Res. 1993 Jun;72(6):1337-44. doi: 10.1161/01.res.72.6.1337.
Pubmed: 7916667
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