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Modulation of cardiac Kv channels by accessory KCNE subunits


Alicia Lundby


Maintenance of rhythmic contractions of the myocardium is essential for the heart to carry out its primary function of delivering oxygenated blood to the systemic circuitry. Myocardial contraction is controlled by an ensemble of electrical currents that can be measured at the single cell level as corresponding action potentials. The action potentials are generated by specialized cells in the
sinoatrial node, and electrical coupling of individual cardiomyocytes ensures rapid propagation of the depolarizing wave front to the whole heart, ultimately resulting in a coordinated contraction of the myocardium. Spatial and temporal variation in action potential shape can be detected across the myocardium, and these variations are important for timely myocardial contraction. Each action potential is associated with an orchestra of currents, and the heterogeneity in action potential morphology is linked to cellular differences in the particular currents embraced in the orchestra.
Among the players involved are depolarization activated potassium (Kv) currents, which are major determinants of action potential amplitude and duration. In most cardiomyocytes two fundamentally different types of Kv currents can be discriminated: a rapidly activating and inactivating outward current underlying the early phase of action potential repolarization (Ito), and a slowly inactivating, outwardly rectifying current underlying the late phase
of membrane repolarization (IK, hereunder IKs). Distinct ion channels and interacting partners constitute the molecular compositions that mediate these currents, and part of the molecular explanation for cellular heterogeneity in cardiac Kv currents is correlated to regional differences in the protein complexes that underlie them. The characteristics of currents conducted by a particular
ion channel complex are dependent upon which accessory proteins assemble with the currentmediating ion channel and modulate its function. The research that forms basis for the present thesis concerns this particular issue, with emphasis on cardiac Kv channel modulation by accessory KCNE subunits. Specifically, putative roles of the KCNE accessory subunits as part of the molecular macrocomplexes constituting the cardiac currents IKs and Ito will be discussed. The thesis consists of a general introduction to ion channels with emphasis on Kv channels, followed by a brief description of the cardiac conduction system and the underlying currents. Focus then turns to modulation of cardiac Kv channels by accessory subunits, and in light of the publications part of the thesis, emphasis is given to KCNE1, KCNE2 and KCNE3 accessory subunits. Specifically, interactions of KCNE1 and KCNE2 subunits with Kv7.1 channels and KCNE3 interactions with Kv4.3 channels is discussed, and speculations regarding their respective importance for IKs and Ito is presented.