Cardiac transient outward potassium current

The cardiac transient outward potassium current (referred to as I_to1 or I_to^[1]) is one of the ion currents across the cell membrane of heart muscle cells. It is responsible for the (brief) repolarizing phase 1 of the cardiac action potential (which suceeds depolarisation, and precedes the plateau phase).^[2] The I_to is produced by movement of positively charged potassium (K⁺) ions from the intracellular into the extracellular space. It exhibits rapid activation and inactivation.^[3] I_to1 is complemented with I_to2 resulting from Cl⁻ ions to form the transient outward current I_to.^{[citation needed]}

The I_to1 is generated by voltage-gated K+ channels Kv1.4, Kv4.2, and (especially) Kv4.3; these channels undergo ball-and-chain inactivation to terminate the current.^[3]

It occurs in atrial, ventricular, and conduction system cells. In ventricular myocardium, it is more potent in the epicardium than the endocardium; this transmural I_to1 gradient underlies the J wave ECG finding.^[3]

Role in disease

Reduction in I_to1 density is associated with prolonged action potentials and is a common finding in cardiac disease.^[4]

I_to1 density is significantly lower in the cells of a failing heart in comparison to the cells of a healthy heart.^[5]
There is correlation between decreased I_to1 density and atrial fibrillation.^[6]
I_to activation is inhibited by thyrotropin (TSH).^[7] This mechanisms may be one of the reasons for the observation that both bradycardia and atrial fibrillation are common in hypothyroidism.^[8]^[9]^[10]

An increase in the I_to1 density caused by a mutation in Kv4.3 can be a cause of Brugada Syndrome.^[11]

References

^ Niwa N, Nerbonne JM (January 2010). "Molecular determinants of cardiac transient outward potassium current (I(to)) expression and regulation". Journal of Molecular and Cellular Cardiology. 48 (1): 12–25. doi:10.1016/j.yjmcc.2009.07.013. PMC 2813406. PMID 19619557.
^ Greger R, Windhorst U (1996). Comprehensive Human Physiology: From Cellular Mechanisms to Integration. Berlin, Heidelberg: Springer. p. 1828. ISBN 978-3-642-60946-6.
^ ^a ^b ^c Asirvatham SJ, ed. (2014). Mayo Clinic Electrophysiology Manual. Oxford: Mayo Clinic Scientific Press/Oxford University Press. p. 174. ISBN 978-0-19-933041-6.
^ Oudit GY, Kassiri Z, Sah R, Ramirez RJ, Zobel C, Backx PH (May 2001). "The molecular physiology of the cardiac transient outward potassium current (I(to)) in normal and diseased myocardium". Journal of Molecular and Cellular Cardiology. 33 (5): 851–872. doi:10.1006/jmcc.2001.1376. PMID 11343410. S2CID 829154.
^ Beuckelmann DJ, Näbauer M, Erdmann E (August 1993). "Alterations of K+ currents in isolated human ventricular myocytes from patients with terminal heart failure". Circulation Research. 73 (2): 379–385. doi:10.1161/01.RES.73.2.379. PMID 8330380.
^ Brandt MC, Priebe L, Böhle T, Südkamp M, Beuckelmann DJ (October 2000). "The ultrarapid and the transient outward K(+) current in human atrial fibrillation. Their possible role in postoperative atrial fibrillation". Journal of Molecular and Cellular Cardiology. 32 (10): 1885–1896. doi:10.1006/jmcc.2000.1221. PMID 11013132.
^ Alonso H, Fernández-Ruocco J, Gallego M, Malagueta-Vieira LL, Rodríguez-de-Yurre A, Medei E, et al. (December 2015). "Thyroid stimulating hormone directly modulates cardiac electrical activity". Journal of Molecular and Cellular Cardiology. 89 (Pt B): 280–286. doi:10.1016/j.yjmcc.2015.10.019. PMID 26497403.
^ Müller P, Leow MK, Dietrich JW (15 August 2022). "Minor perturbations of thyroid homeostasis and major cardiovascular endpoints-Physiological mechanisms and clinical evidence". Frontiers in Cardiovascular Medicine. 9 942971. doi:10.3389/fcvm.2022.942971. PMC 9420854. PMID 36046184.
^ Zhang Y, Dedkov EI, Teplitsky D, Weltman NY, Pol CJ, Rajagopalan V, et al. (October 2013). "Both hypothyroidism and hyperthyroidism increase atrial fibrillation inducibility in rats". Circulation: Arrhythmia and Electrophysiology. 6 (5): 952–959. doi:10.1161/CIRCEP.113.000502. PMC 3973490. PMID 24036190.
^ Kolettis TM, Tsatsoulis A (December 2012). "Subclinical Hypothyroidism: An Overlooked Cause of Atrial Fibrillation?". Journal of Atrial Fibrillation. 5 (4): 710. doi:10.4022/jafib.710 (inactive 11 July 2025). PMC 5153160. PMID 28496796.{{cite journal}}: CS1 maint: DOI inactive as of July 2025 (link)
^ Giudicessi JR, Ye D, Tester DJ, Crotti L, Mugione A, Nesterenko VV, et al. (July 2011). "Transient outward current (I(to)) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome". Heart Rhythm. 8 (7): 1024–1032. doi:10.1016/j.hrthm.2011.02.021. PMC 3150551. PMID 21349352.

[1] Niwa N, Nerbonne JM (January 2010). "Molecular determinants of cardiac transient outward potassium current (I(to)) expression and regulation". Journal of Molecular and Cellular Cardiology. 48 (1): 12–25. doi:10.1016/j.yjmcc.2009.07.013. PMC 2813406. PMID 19619557.

[2] Greger R, Windhorst U (1996). Comprehensive Human Physiology: From Cellular Mechanisms to Integration. Berlin, Heidelberg: Springer. p. 1828. ISBN 978-3-642-60946-6.

[:0-3] Asirvatham SJ, ed. (2014). Mayo Clinic Electrophysiology Manual. Oxford: Mayo Clinic Scientific Press/Oxford University Press. p. 174. ISBN 978-0-19-933041-6.

[oudit-4] Oudit GY, Kassiri Z, Sah R, Ramirez RJ, Zobel C, Backx PH (May 2001). "The molecular physiology of the cardiac transient outward potassium current (I(to)) in normal and diseased myocardium". Journal of Molecular and Cellular Cardiology. 33 (5): 851–872. doi:10.1006/jmcc.2001.1376. PMID 11343410. S2CID 829154.

[5] Beuckelmann DJ, Näbauer M, Erdmann E (August 1993). "Alterations of K+ currents in isolated human ventricular myocytes from patients with terminal heart failure". Circulation Research. 73 (2): 379–385. doi:10.1161/01.RES.73.2.379. PMID 8330380.

[6] Brandt MC, Priebe L, Böhle T, Südkamp M, Beuckelmann DJ (October 2000). "The ultrarapid and the transient outward K(+) current in human atrial fibrillation. Their possible role in postoperative atrial fibrillation". Journal of Molecular and Cellular Cardiology. 32 (10): 1885–1896. doi:10.1006/jmcc.2000.1221. PMID 11013132.

[7] Alonso H, Fernández-Ruocco J, Gallego M, Malagueta-Vieira LL, Rodríguez-de-Yurre A, Medei E, et al. (December 2015). "Thyroid stimulating hormone directly modulates cardiac electrical activity". Journal of Molecular and Cellular Cardiology. 89 (Pt B): 280–286. doi:10.1016/j.yjmcc.2015.10.019. PMID 26497403.

[8] Müller P, Leow MK, Dietrich JW (15 August 2022). "Minor perturbations of thyroid homeostasis and major cardiovascular endpoints-Physiological mechanisms and clinical evidence". Frontiers in Cardiovascular Medicine. 9 942971. doi:10.3389/fcvm.2022.942971. PMC 9420854. PMID 36046184.

[9] Zhang Y, Dedkov EI, Teplitsky D, Weltman NY, Pol CJ, Rajagopalan V, et al. (October 2013). "Both hypothyroidism and hyperthyroidism increase atrial fibrillation inducibility in rats". Circulation: Arrhythmia and Electrophysiology. 6 (5): 952–959. doi:10.1161/CIRCEP.113.000502. PMC 3973490. PMID 24036190.

[10] Kolettis TM, Tsatsoulis A (December 2012). "Subclinical Hypothyroidism: An Overlooked Cause of Atrial Fibrillation?". Journal of Atrial Fibrillation. 5 (4): 710. doi:10.4022/jafib.710 (inactive 11 July 2025). PMC 5153160. PMID 28496796.{{cite journal}}: CS1 maint: DOI inactive as of July 2025 (link)

[11] Giudicessi JR, Ye D, Tester DJ, Crotti L, Mugione A, Nesterenko VV, et al. (July 2011). "Transient outward current (I(to)) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome". Heart Rhythm. 8 (7): 1024–1032. doi:10.1016/j.hrthm.2011.02.021. PMC 3150551. PMID 21349352.

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