Role of Cardiac hERG1 Isoforms single-exponential function. In figure 6A, the resulting restitution curves are shown. For simplicity the exponential fits are not shown. As the relative abundance of hERG1b was increased the restitution curves became gradually flatter. The slope of the restitution curve is associated with electrical stability of cardiac tissue. To study the slope of the curves in more detail, the exponential fits to the restitution curves were differentiated to obtain the slope over the whole range of DIs. The relationships between slope and DI are shown in figure 6B. The figure shows that as the relative abundance of hERG1b was increased the slope of the restitution curve was reduced markedly for DIs shorter than 200 ms. In general, the slope of the restitution curve is dependent on the balance between inward and outward currents immediately before the S2 stimulus is applied. Mechanistically, the reduced slope can therefore be explained by fewer hERG1 channels residing in the open state during late phase 3 and phase 4 of the action potential (figure 5C). Thus, the change in restitution slope is mainly due to the increase in deactivation kinetics resulting from greater hERG1b abundance. Discussion A considerable variation has been observed in the ‘peak potential’ characterizing native IKr transients [10]. This observa- tion may, in theory, be explained by differences in IKr channel kinetics. Intrinsic differences in IKr deactivation kinetics have been described [11] supporting the notion that considerable heteroge- neity in IKr kinetics exists in the heart. Figure 5. Action potential duration is modulated by the relative abundance of hERG1a and hERG1b. A, Steady-state action potentials simulated by the modified ten Tusscher (TTF) model paced at a basic cycle length (BCL) of 1000 ms. The transition rates of hERG1 channel activation (a3), deactivation (b3) and recovery from inactivation (b4) were modified to represent a gradual increase in the relative abundance of hERG1b (see table S2 for details). B, Simulated IKr corresponding to the action potentials shown in A. Legend is the same as in A. C and D, Channel state occupancy during the action potential is shown for the open and inactivated states respectively. Legend is the same as in A. doi:10.1371/journal.pone.0009021.g005 Figure 6. Restitution slope is modulated by the relative abundance of hERG1a and hERG1b. A, Single-cell action potential restitution. The restitution curves were obtained using an S1-S2 restitution protocol measured at a BCL of 1000 ms. The action potential duration (APD90) is plotted as a function of the diastolic interval (DI). The transition rates of hERG1 channel activation (a3), deactivation (b3) and recovery from inactivation (b4) were modified to represent a gradual increase in the relative abundance of hERG1b (see table S2 for details). B, The slopes of the restitution curves were calculated by differentiation of single-exponential functions fitted to the curves in A and plotted as a function of DI. doi:10.1371/journal.pone.0009021.g006 PLoS ONE | www.plosone.org 6 February 2010 | Volume 5 | Issue 2 | e9021