Mechanisms contributing to myocardial potassium channel diversity, regulation and remodeling

Abstract

In the mammalian heart, multiple types of K+ channels contribute to the control of cardiac electrical and mechanical functioning through the regulation of resting membrane potentials, action potential waveforms and refractoriness. There are similarly vast arrays of K+ channel pore-forming and accessory subunits that contribute to the generation of functional myocardial K+ channel diversity. Maladaptive remodeling of K+ channels associated with cardiac and systemic diseases results in impaired repolarization and increased propensity for arrhythmias. Here, we review the diverse transcriptional, post-transcriptional, post-translational and epigenetic mechanisms contributing to regulating the expression, distribution and remodeling of cardiac K+ channels under physiological and pathological conditions.

RNAs that make a heart beat

“…During cardiac action potentials, there is a flux of sodium (Na + ) into the cell, along with an inward flux of calcium (Ca + ), that leads to the depolarization, followed by outward potassium (K + ) currents that repolarize the cell (1,(8)(9)(10)(11)). …”

“…The expression and regulation of these potassium channels, for instance, in different positions within the heart, can lead to changes in action potential amplitude, duration, waveforms, and rhythmicity (8,12). The transient voltagegated potassium current (I to ) in phase one is sometimes divided into I to,fast and I to,slow based on the rate of recovery (20-100 ms for the fast current and seconds for the slow current) (11).…”

“…Abnormalities in the repolarization phase of action potentials due to heart failure can contribute to arrhythmias (11,18). Dramatic changes in the levels and properties of myocardial potassium currents have been observed with cardiac disease (8), including myocardial infarction, the death and destruction of heart muscle as a result of lack of oxygen. In canine models of myocardial infarction, potassium currents are down-regulated in cells in the infarcted zone (19)(20)(21), that is, the portion of tissue that is dying or dead due to lack of blood supply.…”

“…Transcriptional regulation plays an important role in the proper expression of different potassium channel components (8).…”

“…Other mechanisms that regulate potassium channel activity include splicing, RNA editing, and post-translational modifications such as phosphorylation (8,11). In addition, microRNAs have been demonstrated as post-transcriptional regulators of potassium channel expression (2).…”