Kir2.1 & Nav1.5 in Sickness and in Health
Who Needs a Chaperone When They Have an Alpha Partner?
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The ventricular action potential is sculpted by the orchestrated activity of multiple depolarizing and repolarizing ion currents, exchangers, and pumps. Owing to the time and voltage dependency of these ion transport mechanisms, even a subtle change in one will influence the activity of the others. This, in turn, will profoundly impact the electrophysiological properties of the myocyte and the heart as a whole. Indeed, altered ion channel activity in response to pharmacological agents, acquired diseases, or congenital disorders is a major cause of malignant ventricular arrhythmias leading to sudden cardiac death.1
Article, see p 1501
Chief among the many cardiac ion currents that generate the action potential are the inward rectifier K current (IK1) and the voltage-gated fast inward Na current (INa), along with their pore-forming α subunits, Kir2.1 and Nav1.5.2 The relative importance of these 2 channels is underscored by the tight control that they exert on myocyte excitability. Whereas IK1 establishes the resting membrane potential, INa is responsible for generating the action potential upstroke (or phase 0). Because the driving force for INa is fueled by the difference in voltage between the resting membrane potential and the reversal potential for Na, IK1 exerts primary control over myocyte excitability and secondary control over action potential formation and propagation. The relevance of the functional interplay between IK1 and INa extends beyond the regulation of normal excitability because it plays a particularly important role in pathophysiological situations, such as hyperkalemia and ischemia. In both settings, membrane depolarization reduces INa and promotes its partial inactivation.
In addition to the indirect …