Action potential waveforms and propagation in the mammalian myocardium. A: Schematic representation of action potential waveforms recorded in different regions of the human heart; action potentials are displaced in time to reflect the temporal sequence of propagation. B: Schematic of a ventricular action potential labeled as follows: (0) depolarization; 1 early (fast) repolarization, which results in the “notch”; 2 plateau phase; 3 late (slower) phase of repolarization; and, 4 afterhyperpolarization/return to the resting membrane potential. C: Configuration of a typical scalar electrocardiogram with the various deflections (P, Q, R, S, T) and intervals (PR, QRS, QT) marked; QT intervals, however, must be corrected for variations in heart rate (see text).

Differential expression of the transient outward K⁺ currents, I_to,f and I_to,s in mouse left ventricular myocytes. A: Whole‐cell outward K⁺ currents recorded from isolated adult C57BL6 mouse right ventricular (RV) myocytes and from left ventricular (LV) cells from the apex or septum; currents recorded in response to 4.5 sec depolarizing voltage steps from a holding potential of −70 mV to potentials between −20 and +60 mV in 20 mV increments are shown. As is evident, peak outward K⁺ densities are highest in RV myocytes, and peak outward K⁺ current densities are higher in cells from the apex than from septum. In addition, the decay phases of the currents are slower in LV septum, than LV apex or RV, cells. B: Mean ± SEM activation time constants, determined from single exponential fits to the rising phases of the currents, are plotted as a function of test potential; the solid lines represent the best single exponential fits to the data points and describe the voltage‐dependence of current activation. The rates of activation of I_to,f, I_to,s, and I_K(slow) in mouse ventricular myocytes are similar, whereas I_ss activates more slowly. C: Mean ± SEM inactivation time constants (determined from double or triple exponential fits to the decay phases of the outward currents) for I_to,f, I_to,s and I_K(slow) are plotted as a function of test potential. D: Mean ± SEM normalized recovery data for I_to,f, I_to,s, and I_K(slow). The rates of recovery of I_to,f, I_to,s and I_K(slow) from steady‐state inactivation were determined using a three‐pulse protocol: cells were first depolarized to + 50 mV for 5 sec (to inactivate the currents), hyperpolarized to −70 mV for varying times (to allow recovery) and subsequently depolarized to +50 mV (to assess the extent of recovery). The amplitudes of I_to,f, I_to,s and I_K(slow) evoked at +50 mV following each recovery period were then determined, and normalized to the current amplitudes evoked following the 10 sec recovery period. As is evident, I_to,f recovers very rapidly from inactivation, whereas I_to,s and I_K(slow)) recover slowly.

Structure, expression and assembly of voltage‐gated K⁺ channel pore‐forming (α) subunits. A: Voltage‐gated K⁺ channel α subunits are integral membrane proteins with six transmembrane domains, intracellular N‐ and C‐termini, and a positively charged S4 region, placing them in the “S4 superfamily” of voltage‐gated ion channels. B: Alternative splicing of Kv α subunits will give rise to proteins with novel N‐and C‐termini that produce voltage‐gated K⁺ currents with distinct properties. C: Voltage‐gated outward K⁺ currents are produced on heterologous expression of Kv α subunits. In some cases, such as Kv4.2 illustrated here, the currents are rapidly activating and inactivating. Outward K⁺ currents with distinct time‐ and voltage‐dependent properties are observed on heterologous expression of the various Kv1.x, Kv2.x, Kv3.x, and Kv4.x subfamily members. D: Schematic of a “functional” voltage‐gated K⁺ channel illustrating four Kv α subunits contributing to a K⁺ selective pore.

Accessory subunits and the formation of functional voltage‐gated K⁺ channels. A: Putative membrane topology and subunit composition of voltage‐gated K⁺ myocardial channels with minK (miRP1) or accessory β subunits. Although Kv α and β subunits appear to associate in 1:1 ratios, the functional stoichiometry of minK‐ and KvLQT1‐(or MiRP1‐ERG1)‐containing K⁺ channels has not been defined. B: Representations of voltage‐gated K⁺ channel biogenesis and interactions with the cytoskeleton. Channel biosynthesis and assembly occur in the endoplasmic reticulum, and accessory β and regulatory KChAP (KChIP) subunits appear to play roles in mediating the biochemical maturation of functional voltage‐gated K⁺ channels, as well as in regulating the cell surface expression of these channels. In addition to associations with β subunits/minK and/or the KChAPs/KChIPs, it has recently been suggested that voltage‐gated K⁺ channel α subunits also interact directly with cytoskeletal proteins, including α‐actinin‐2 and PDZ‐binding domain proteins that function to link the channels to the actin cytoskeleton.

Molecular genetic dissection of the transient outward K⁺ currents I_lo,f and I_to,s in mouse ventricular myocytes. Representative outward K⁺ current waveforms recorded from adult C57BL6 mouse left ventricular (LV) apex and septum cells in response to 4.5 sec depolarizing voltage steps to −20 to + 50 mV from a holding potential of −70 mV (compare with Fig. 2A). Records from wild‐type, Kv4.2W362F‐expressing, Kv1.4‐/‐and Kv4.2W362F X Kv1.4‐/‐LV cells are displayed. Expression of Kv4.2W362F results in the loss of I_to,f, whereas targeted deletion of Kv1.4 eliminates I_to,s. Both I_to,f and I_to,s, however, are absent in cells from the Kv4.2W362F X Kv1.4‐/‐crossed animals, and the waveforms of the outward currents in LV apex and septum (from these animals) are indistinguishable.

QT prolongation in mice lacking I_to,f, I_to,s or both I_to,f and I_to,s. Telemetric ECG recordings were obtained from conscious adult C57BL6 mice with the phenotypes indicated. QT intervals were determined using cursors, one placed at the beginning of the QRS complex and the other placed where the T wave voltage crosses the baseline. As is evident in the left panel, the QT interval is markedly prolonged in Kv4.2W362F X Kv1.4‐/‐mice compared with wild‐type Kv1.4‐/‐or Kv4.2W362F‐expressing animals. Average QT intervals and heart rates in individual (3 min) recording episodes were determined, and each point is represented (right panel). The variation in the observed QT intervals with heart rate in wild‐type, Kv4.2W362F‐Kv1.4‐/‐and Kv4.2W362F X Kv1.4‐/‐animals are plotted in the right panel. As expected, QT intervals vary with heart rate and must be corrected (QTc) for differences in rates (see text). The difference between Kv4.2W362F‐expressing and Kv4.2W362F X Kv1.4‐/‐mice is evident over a wild range of heart rates.

Functional consequences of changes in repolarizing voltage‐gated K⁺ currents. Atrioventricular block (A, B) and ventricular tachycardia (C, D) are evident in mice in which functional voltage‐gated K⁺ channel densities have been manipulated. Recordings illustrated were from Kv4.2W362F X Kv1.4‐/‐ (A, B, D) and Kv1.1N206Tag‐(C) expressing animals. A: Recordings from a Kv4.2W362F X Kv1.4‐/‐ mouse showing Mobitz type I second‐degree atrioventricular block, and occasionally (B) high‐degree atrioventricular block with multiple sequential dropped beats. B: Note that the QRS complex (indicated by the *) was generated by the subsidiary pacemaker. C: Surface EGG recording of an 11‐beat run of ventricular tacchycardia in a Kv1.1N206Tag‐expressing adult mouse. The sinus rate here was 530 beats per minute, and the rate of the ventricular tacchycardia was 570 beats per minute. D: Telemetric recording of a 7‐beat run of ventricular tacchycardia in a Kv4.2W362F X Kv1.4‐/‐ mouse. In both C and D, note the widened QRS complexes during nonsustained ventricular taccycardia.