Regulation of cardiac excitation-contraction coupling by action potential repolarization: role of the transient outward potassium current (I(to))

Abstract

The cardiac action potential (AP) is critical for initiating and coordinating myocyte contraction. In particular, the early repolarization period of the AP (phase 1) strongly influences the time course and magnitude of the whole-cell intracellular Ca(2+) transient by modulating trans-sarcolemmal Ca(2+) influx through L-type Ca(2+) channels (I(Ca,L)) and Na-Ca exchangers (I(Ca,NCX)). The transient outward potassium current (I(to)) has kinetic properties that make it especially effective in modulating the trajectory of phase 1 repolarization and thereby cardiac excitation-contraction coupling (ECC). The magnitude of I(to) varies greatly during cardiac development, between different regions of the heart, and is invariably reduced as a result of heart disease, leading to corresponding variations in ECC. In this article, we review evidence supporting a modulatory role of I(to) in ECC through its influence on I(Ca,L), and possibly I(Ca,NCX). We also discuss differential effects of I(to) on ECC between different species, between different regions of the heart and in heart disease.

Figure 1. Sites of regulation of SR Ca²⁺ release in cardiac myocytes

SR Ca²⁺ load (1) is maintained by Ca²⁺ uptake via the SR Ca²⁺ ATPase (SERCA2a), which is modulated through its interaction with phospholamban (PLN) and sarcolipin (SLN). Passive leak through ryanodine receptors (RyR) also plays a role in regulating steady-state SR Ca²⁺ content. The SR Ca²⁺ load determines the amount of Ca²⁺ released and the sensitivity of the RyR release mechanism to trigger Ca²⁺. This trigger Ca²⁺ enters primarily via L-type Ca²⁺ channels (2), while Ca²⁺ influx via reverse-mode Na⁺-Ca²⁺ exchange (3) may secondarily contribute to Ca²⁺-induced Ca²⁺-release. Since both L-type Ca²⁺ channel gating and Na⁺-Ca²⁺ exchange activity are voltage dependent, we propose that altering early repolarization of the action potential via changes in transient outward potassium current (I_to) magnitude may play a role in modulating SR Ca²⁺ release.

Figure 2. Effect of transient outward potassium current elimination on murine and canine AP profile

A, AP measured in current-clamp mode from a control mouse myocyte (left) and Kv4.2N transgenic mouse myocyte (right). Kv4.2N-expressing myocytes have reduced I_to densities and prolonged APs compared to controls. B, AP generated from a canine computer model (Greenstein et al. 2000) with control I_to levels (conductance = 0.12 nS pF⁻¹; left) and elimination of I_to (right). Removal of I_to markedly slows early repolarization, abolishes the AP notch, and shortens the overall AP duration (APD_{90,G = 0.12} = 300 ms, APD_{90,G = 0} = 250 ms) in canine APs. Note the difference in time scale between the canine and murine APs. Canine APs were generated using the interactive version of the Winslow-Rice-Jafri canine myocyte model (Greenstein et al. 2000).

Figure 3. Effect of repolarization rate on I_Ca,L and [Ca²⁺]

A, stimulus ramps of 5, 50, 200 and 500 ms duration were applied to rat ventricular myocytes. B, representative I_Ca,L traces triggered by voltage ramps shown in A above. C, peak intracellular Ca²⁺ triggered by the voltage ramps above show a biphasic relationship with respect to repolarization rate, increasing from the 5 ms to 50 ms ramp and decreasing thereafter. The rates of rise of the Ca²⁺ transients are also slowed as repolarization is prolonged. Note the difference in time scale between panel C and panels A and B.

Figure 5. Effect of fast and slow phase 1 AP repolarization on I_Ca,L and Ca²⁺ spikes

A, fast (left) and slow (right) phase 1 AP waveforms were applied to rat ventricular myocytes. B, representative I_Ca,L traces in myocytes stimulated with the AP shown above. C, 600 ms surface plots generated from confocal line scans show loss of recruitment and temporal synchronization of Ca²⁺ release events in myocytes stimulated with slow phase 1 APs.

Figure 4. Putative mechanism responsible for biphasic dependence of SR Ca²⁺ release on repolarization rates

The mechanisms describing the ascending portion of the relationship (grey dashed lines; left side of diagram) may dominate in species with short, triangular APs, while species with longer, notched AP morphologies may operate primarily on the descending portion (black continuous lines; right side of diagram) and may be governed by different parameters of I_Ca,L.

Figure 6. Slowed repolarization produces a similar pattern of Ca²⁺ release to that observed in disease

A, 1.6 s line scans taken during 50 ms (left) and 500 ms (right) voltage ramps following a train of eight 100 ms steps to +10 mV in rat ventricular myocytes. With the 500 ms ramp, Ca²⁺ release was sufficiently asynchronous to resolve individual Ca²⁺ sparks and the rise and decay of the Ca²⁺ transient (continuous line below) was significantly slowed relative to that of the 50 ms ramp. This pattern of Ca²⁺ release is strikingly similar to recent findings in myocytes from infarcted rabbit hearts (MI) (Litwin, 2000), shown in panel B below. B, confocal line scans and derived Ca²⁺ transients (below) from control (left) and MI (right) rabbit myocytes. Reproduced with permission from Circulation Research.