Targeting Potassium Channel Trafficking in Cardiac Arrhythmia

Abstract

determines cardiac systolic/diastolic function, and abnormalities could result in cardiac arrhythmia and even sudden cardiac death (Hoffman and Cranefield, 1960).Chapter 1 2. Phase 1 is a phase of rapid repolarization beginning with rapid inactivation of voltage-gated Na + channels that aborts inward INa. At the same time, a transient outward K + current, Ito (Rudy, 2008), by activating voltage-gated K + channels briefly, leads to a slight negative shift of membrane potential (Santana et al., 2010; Grant, 2009). 3. Phase 2 is the plateau phase. The slow delayed rectifier K + current, IKs is slowly activated allowing K + efflux, which is partially balanced by the inward ICa,L activated at phase 0. Moreover, the increased concentration of intracellular Ca 2+ also activates Ca 2+ channels on the sarcoplasmic reticulum (SR), the so-called Ryanodine receptors, allowing Ca 2+ efflux move from SR to cytoplasm, a Ca 2+ activated Clcurrent (Hoffman, 1960) allowing Cl − into the cell, and ionic pumps like Na + -Ca 2+ exchanger and Na + -K + pump. All these ionic movements result in the membrane potential remaining almost constant with a low level of membrane repolarizing (Grant, 2009; Grunnet, 2010). 4. Phase 3 is the phase of rapid repolarization because L-type Ca 2+ channels close, while IKs remains activated and the negative change in membrane potential induces more K + currents, primarily the rapid delayed rectifier K + current (IKr) and the inward rectifier K + current (IK1). The strong outward K + current brings the membrane potential back to its resting value. The voltage-gated delayed rectifier K + channels close at ~-85 mV, while IK1 remains active and helps to maintain the resting membrane potential (Grant, 2009; Kubo et al., 2005). 5. Phase 4 represents the resting phase. The resting membrane potential is stable and more or less constant at ~-80 mV, resulting from perfect balance between influx of ions (e.g. Na + and Ca 2+ ) and efflux of ions (e.g. K + , Cland HCO3 -) (Santana, 2010; Morad and Tung, 1982). Among these ion channels, the potassium channel family is the largest branch. It can be broadly divided into two subfamilies by its transmembrane structure features: the six-transmembrane-helix voltage-gated potassium channel (Kv) and the two-transmembrane-helix inward rectifier potassium channel (KIR) (Ho et al., 1993).