Small and Intermediate Calcium Activated Potassium Channels in the Heart: Role and Strategies in the Treatment of Cardiovascular Diseases

Figures

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  FIGURE 1. Representative cartoon of a SK4 α-subunit in absence of calcium. Each monomer is formed by six transmembrane domains (S1–S6), which are prolonged by cytoplasmic N and C termini. S4 is the voltage sensor, with positively charged amino acids. The segment (P-loop) between S5 and S6 forms the pore of SK4 and includes the GYG “selectivity filter” for potassium. The Calmodulin binding domain (HA and HB helixes), binds Calmodulin on the C-lobes. In low [Ca2+]i conditions, the N-lobes of Calmodulin are free and positioned closely to the S2-S3 intracellular segment. Helix C, toward the cytosol is involved in the assembly of the α-subunits as a functional channel.

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  FIGURE 2. General model of the pacemaker currents in SAN and their relation with SK and IK channels. During the late repolarization of the previous action potential, SK4 are still opened and their outward currents (4) act like a MDP driving force (4), which concurrently activates HCN channels (If current). The gradual depolarization recruits other conductances such as Ib, Na, ICaT (3.1 and 3.2), ITRPM4 and ITRPM7, which, altogether in synergy, are responsible for the diastolic depolarization (1). In parallel, diastolic sarcoplasmic spontaneous calcium release through RyR receptors increases the cytoplasmic level of calcium and activates the NCX-1 exchanger in its forward mode (1). The progressive Ca2+ extrusion operated by NCX from early to late DD gradually reduces IKCa and allows inward currents to take over. INCX, together with the other described currents, depolarize the membrane until the threshold of activation for L-type Ca2+ channels (ICa,L) and AP ignition (2). During the early repolarization, high [Ca2+]i open small SK channels (3) which contribute to this phase of the action potential. The progressive cytosolic decrease of calcium (SR reuptake and extrusion) decreases SK…

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  FIGURE 3. Involvement of IK and SK in cardiovascular diseases and potential therapeutic strategies. For each condition (early stage Atrial Fibrillation, Ventricular arrhythmia, Myocardial Infarction and Heart Failure), a healthy action potential is shown (black cartoon) in comparison with the altered one (red cartoon). The different positive (green) or negative (red) effects based on ISKCa and IKCa modulations are summarized. PPi, P wave Interval; aERP, atrial effective refractory period; PRi, P-R segment; H.R, heart rate; DADs, delayed after depolarization; VPC, ventricular premature contraction; NSVT, non-sustained ventricular tachycardia; LVESV, left ventricular end-systolic volume; CRT, cardiac resynchronization therapy; IKr, rapid activating delayed rectifier potassium current; IKs, slow activating delayed rectifier potassium current; Ito, voltage-gated transient outward potassium current; INCX, sodium-calcium exchanger current.