Molecular Physiology of Cardiac Repolarization

Abstract

The heart is a rhythmic electromechanical pump, the functioning of which depends on action potential generation and propagation, followed by relaxation and a period of refractoriness until the next impulse is generated. Myocardial action potentials reflect the sequential activation and inactivation of inward (Na(+) and Ca(2+)) and outward (K(+)) current carrying ion channels. In different regions of the heart, action potential waveforms are distinct, owing to differences in Na(+), Ca(2+), and K(+) channel expression, and these differences contribute to the normal, unidirectional propagation of activity and to the generation of normal cardiac rhythms. Changes in channel functioning, resulting from inherited or acquired disease, affect action potential repolarization and can lead to the generation of life-threatening arrhythmias. There is, therefore, considerable interest in understanding the mechanisms that control cardiac repolarization and rhythm generation. Electrophysiological studies have detailed the properties of the Na(+), Ca(2+), and K(+) currents that generate cardiac action potentials, and molecular cloning has revealed a large number of pore forming (alpha) and accessory (beta, delta, and gamma) subunits thought to contribute to the formation of these channels. Considerable progress has been made in defining the functional roles of the various channels and in identifying the alpha-subunits encoding these channels. Much less is known, however, about the functioning of channel accessory subunits and/or posttranslational processing of the channel proteins. It has also become clear that cardiac ion channels function as components of macromolecular complexes, comprising the alpha-subunits, one or more accessory subunit, and a variety of other regulatory proteins. In addition, these macromolecular channel protein complexes appear to interact with the actin cytoskeleton and/or the extracellular matrix, suggesting important functional links between channel complexes, as well as between cardiac structure and electrical functioning. Important areas of future research will be the identification of (all of) the molecular components of functional cardiac ion channels and delineation of the molecular mechanisms involved in regulating the expression and the functioning of these channels in the normal and the diseased myocardium.

Oxidoreductase regulation of Kv currents in rat ventricle

“…5A) and RA (Fig. 6A) blocked the effect of DCA to up-regulate I peak after diamide it is likely that the thioredoxin system controls Kv channels underlying this current, most likely Kv4.2, Kv4.3, and possibly Kv1.4 [43]. In contrast, the response of I ss to DCA after diamide was not altered by TrxR inhibitors (Fig.…”

“…6B). Since Kv1.5 and Kv2.1 channels largely contribute to I ss in rat myocytes [43], it may be postulated that one or both are regulated by the glutaredoxin system, although accessory subunits may also be involved. Given that BCNU inhibits TrxR and GR to a similar degree (Fig.…”

The Impact of Heterozygous KCNK3 Mutations Associated With Pulmonary Arterial Hypertension on Channel Function and Pharmacological Recovery

“…In well‐studied channelopathies, mechanisms of dysfunction include defects in trafficking, channel assembly, and electrophysiological function, dependent on the location of the mutation 27, 28…”

Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals

“…Alternatively, or in addition, potassium current may play a functional role, as changes in potassium channel availability can dramatically alter the cardiac action potential [31]. Intriguingly, studies using heterologous expression systems have suggested that β1 may associate with and modulate, K v 4.3, which contributes to transient outward current (I to ) in human and mouse ventricle [32,33]. This interesting possibility will be the focus of future studies.…”