Kv4.3 is an A-type voltage-gated potassium channel that is characterized by fast activation at subthreshold membrane potentials, rapid inactivation, and quick recovery from inactivation. Kv4.3 is responsible for the generation of the transient subthreshold somatodendritic A-type potassium current (I_SA) in neurons and the transient outward potassium current (I_to) in cardiomyocytes. Dysfunction of Kv4.3 is related to a variety of neurological and cardiac diseases, such as pain, epilepsy, hypertrophy, heart failure, myocardial infarction, and heart valvular disease. Two families of accessory subunits, KChIPs (Kv Channel-Interacting Proteins) and DPLPs (Dipeptidyl-Peptidase-Like-Proteins), regulate the gating kinetics, cell surface expression, and subcellular localization of Kv4.3. How KChIPs and DPLPs bind Kv4.3 and regulate its gating properties remains elusive, due to the lack of high-resolution structures of Kv4.3-KChIP and Kv4.3-DPLP complexes.

Recently, the research team led by Prof. GUO Jiangtao from Zhejiang University School of Medicine determined four structures of human Kv4.3, namely Kv4.3 alone, Kv4.3-KChIP1 complex, Kv4.3-KChIP2 complex, and Kv4.3-KChIP1-DPP6 complex. Kv4.3 is in an open state with an activated voltage-sensing domain. In the structures of Kv4.3-KChIP1 complex and Kv4.3-KChIP2 complex, the N-terminal domain and the C-terminal domain of Kv4.3, which are involved in the channel inactivation, are sequestered by KChIP1 or KChIP2, elucidating how KChIP1 and KChIP2 slow the initial fast inactivation and accelerate recovery from inactivation of Kv4.3. In the structure of the Kv4.3-KChIP1-DPP6 complex, the transmembrane helix of DPP6 interacts and stabilizes S1 and S2 in the voltage-sensing domain, likely enhancing the channel’s voltage sensitivity, which can explain why DPLPs are able to modulate Kv4.3 gating by shifting the voltage dependence of activation and inactivation toward more negative membrane potentials. These structures provide insights into the complex gating modulation of Kv4.3 by different auxiliary subunits.

Fig.1 Structures of Kv4.3 alone, Kv4.3-KChIP1, Kv4.3-KChIP2, and Kv4.3-KChIP1-DPP6 complexes.