Kv4 subunits are the main pore-forming proteins responsible for the fast transient outward currents observed in the CNS (rat brain), where they have been described as "A’ currents (IA) and in mammalian heart, where they are known as Ca2+-independent fast outward currents (Ito,f.). Although in human heart the predominant subunit responsible for Ito,f is Kv4.3, in order to reconstitute all the properties of the native current co-expression with an auxiliary protein KChIP (Kv Channel Interacting Protein) is required. These small molecular weight Ca2+-binding proteins typically increase cell surface expression of the channel complex, accelerate the rate of decay of the current at depolarized potentials, and increase the rate of recovery from inactivation at hyperpolarized potentials, i.e. the kinetics then more closely resembles native Ito than if Kv4.3 subunits were expressed alone. The predominant KChIP found in heart is KChIP2 and can exist as various isoforms. The isoform co-expressed with Kv4.3 subunits in this cell line is KChiP2b but will simply be referred to as KChIP2 in this document. In the heart, Ito,f is primarily responsible for the "notch’ during phase 1 of the cardiac action potential. Since it is an early repolarizing current it is of crucial importance in shaping the final cardiac action potential waveform. In the human heart the density of Ito,f is highest in the epicardium and lowest in the endocardium; regional differences controlled by the level of KChiP2 expression. These regional differences significantly contribute to the transmural voltage gradient across the myocardial wall, necessary for normal ventricular activity. Abolishing KChIP2 expression has been shown in mice to markedly affect this gradient with the consequence of increased susceptibility to arrhythmia.
A-type (transient outward) potassium channel activity; ER retention sequence binding; calcium ion binding; identical protein binding; potassium channel activity; protein N-terminus binding; protein binding; voltage-gated ion channel activity;