Cardiac transient outward potassium current explained

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 the main contributing current during the repolarizing phase 1 of the cardiac action potential. It is a result of the movement of positively charged potassium (K⁺) ions from the intracellular to the extracellular space. I_to1 is complemented with I_to2 resulting from Cl⁻ ions to form the transient outward current I_to.

Mechanism

I_to1 is rapidly activated and deactivated.^[2] It is activated after the fast increase of the membrane potential following the phase 0 of the cardiac action potential. Once activated, (K⁺) ions from inside the cells flow to the extracellular space. This outward flow of positively charged ions constitutes the I_to1 and causes the transmembrane voltage to decrease. This decrease of the transmembrane potential is known as repolarization. I_to1 is then quickly deactivated, stopping the repolarization and ending the phase 1 of the action potential.

I_to1 is Ca²⁺-independent^[3] and has been clearly demonstrated in myocytes from different cardiac regions and species.^[3] There are two kinetic variants of cardiac I_to1: fast I_to1, called I_to1,f, and slow Ito, called I_to1,s. The channel responsible for I_to1,f is formed by assembly of Kv4.2 (KCND2) subunits, Kv4.3 (KCND3) subunits or a combination of the two, while the channel responsible for I_to1,s is composed of Kv1.4 (KCNA4) subunits.^[2] In addition, several regulatory subunits and pathways modulating the level and biophysical properties of cardiac I_to have been identified.^[2]

I_to1 affects the opening of Ca²⁺ channels during Phase 2 of the Action Potential. As a result, changes in I_to1 modulate changes in the action potential duration.^[2]

Role in disease

• Reduction in I_to1 density is associated with prolonged action potentials and is a common finding in cardiac disease .^[3]

• I_to1 density is significantly lower in the cells of a failing heart in comparison to the cells of a healthy heart.^[4]

• There is correlation between decreased I_to1 density and atrial fibrillation.^[5]

• I_to activation is inhibited by thyrotropin (TSH).^[6] This mechanisms may be one of the reasons for the observation that both bradycardia and atrial fibrillation are common in hypothyroidism.^{[7] [8] [9]}
• An increase in the I_to1 density caused by a mutation in Kv4.3 can be a cause of Brugada Syndrome.^[10]

Notes and References

1. Niwa. Noriko. Nerbonne, Jeanne M.. Molecular determinants of cardiac transient outward potassium current (Ito) expression and regulation. Journal of Molecular and Cellular Cardiology. January 2010. 48. 1. 12–25. 10.1016/j.yjmcc.2009.07.013. 19619557. 2813406.
2. Wettwer. E.. Amos, G. . Gath, J. . Zerkowski, H.-R. . Reidemeister, J.-C. . Ravens, U. . Transient outward current in human and rat ventricular myocytes. Cardiovascular Research. 1 September 1993. 27. 9. 1662–1669. 10.1093/cvr/27.9.1662. 8287446.
3. Oudit GY, Kassiri Z, Sah R, Ramirez RJ, Zobel C, Backx PH . 829154 . The molecular physiology of the cardiac transient outward potassium current (I(to)) in normal and diseased myocardium . J. Mol. Cell. Cardiol. . 33 . 5 . 851–72 . May 2001 . 11343410 . 10.1006/jmcc.2001.1376 .
4. Beuckelmann. D. J.. Nabauer, M. . Erdmann, E. . Alterations of K+ currents in isolated human ventricular myocytes from patients with terminal heart failure. Circulation Research. 1 August 1993. 73. 2. 379–385. 10.1161/01.RES.73.2.379. 8330380. free.
5. Brandt. M. 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. October 2000. 32. 10. 1885–1896. 10.1006/jmcc.2000.1221. 11013132.
6. Alonso . H . Fernández-Ruocco . J . Gallego . M . Malagueta-Vieira . LL . Rodríguez-de-Yurre . A . Medei . E . Casis . O . Thyroid stimulating hormone directly modulates cardiac electrical activity. . Journal of Molecular and Cellular Cardiology . December 2015 . 89 . Pt B . 280–6 . 10.1016/j.yjmcc.2015.10.019 . 26497403. free .
7. Müller . Patrick . Leow . Melvin Khee-Shing . Dietrich . Johannes W. . Minor perturbations of thyroid homeostasis and major cardiovascular endpoints—Physiological mechanisms and clinical evidence . Frontiers in Cardiovascular Medicine . 15 August 2022 . 9 . 942971 . 10.3389/fcvm.2022.942971. 36046184. 9420854 . free .
8. Zhang . Y . Dedkov . EI . Teplitsky . D . Weltman . NY . Pol . CJ . Rajagopalan . V . Lee . B . Gerdes . AM . Both hypothyroidism and hyperthyroidism increase atrial fibrillation inducibility in rats. . Circulation: Arrhythmia and Electrophysiology . October 2013 . 6 . 5 . 952–9 . 10.1161/CIRCEP.113.000502 . 24036190. 3973490 .
9. Kolettis . TM . Tsatsoulis . A . Subclinical Hypothyroidism: An Overlooked Cause of Atrial Fibrillation? . Journal of Atrial Fibrillation . December 2012 . 5 . 4 . 710 . 10.4022/jafib.710 . 31 January 2024 . 28496796. 5153160 .
10. Giudicessi. John R.. Ye, Dan . Tester, David J. . Crotti, Lia . Mugione, Alessandra . Nesterenko, Vladislav V. . Albertson, Richard M. . Antzelevitch, Charles . Schwartz, Peter J. . Ackerman, Michael J. . Transient outward current (Ito) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome. Heart Rhythm. July 2011. 8. 7. 1024–1032. 10.1016/j.hrthm.2011.02.021. 21349352. 3150551.