Abstract 2334: KChIP2 Functions as a Chaperone, Not as an Accessory Subunit, to Regulate Functional Cell Surface Expression of Kv4-Encoded Myocardial Ito Channels
Background: The fast transient K+ current (Ito,f) determines phase 1 repolarization and underlies the physiologic gradient of ventricular repolarization. Ito,f down regulation is prevalent in the hypertrophied and failing heart, and is associated with lethal ventricular arrhythmias. Accumulating evidence suggests that the reduction in Ito,f does not reflect changes in the transcripts encoding Ito,f pore forming (Kv4) or accessory (KChIP2) subunits, but rather translational or post-translational events.
Methods and Results: Kv currents recorded from left ventricular (LV) myocytes from (KChIP2 −/−) mice with a disruption in the Kcnip2 locus revealed the elimination of Ito,f (Figure 1B⇓) and loss of Kv4.2 protein without reduction in Kcnd2 (Kv4.2) transcript. These findings parallel observations in Kv4.2 −/− LV myocytes, which also lack Ito,f (Figure 1C⇓) and in which KChIP2 protein is reduced by ≥90%, revealing that the mutual stabilization of Kv4.2 and KChIP2 proteins is required for the generation of Ito,f channels. Biochemical studies reveal that interaction between KChIP2 and the distal N-terminal 23 residues of Kv4.2 is required (Figure 1F–G⇓). Adenoviral mediated rescue of Kv4.2 in KChIP2 −/− (and Kv4.2 −/−) LV myocytes (Figure 1D–E⇓) results in rapidly activating and inactivating currents with properties similar to Ito,f, suggesting that KChIP2 does not modify Ito,f kinetics.
Conclusion: KChIP2-Kv4.2 binding stabilizes the protein complex and facilitates the trafficking and surface expression of Ito,f channels. Targeting the KChIP2-Kv4 interacting domain to increase Ito,f channel stability could potentially aid in the treatment of multiple cardiac pathologies.