Kv4.3 is an A-type voltage-gated potassiumchannel that is characterized by fast activation at subthreshold membranepotentials, rapid inactivation, and quick recovery from inactivation. Kv4.3 isresponsible for the generation of the transient subthreshold somatodendriticA-type potassium current (ISA)in neurons and the transient outward potassium current (Ito) in cardiomyocytes. Dysfunction of Kv4.3 is relatedto a variety of neurological and cardiac diseases, such as pain, epilepsy,hypertrophy, heart failure, myocardial infarction, and heart valvular disease. Twofamilies of accessory subunits, KChIPs (Kv Channel-Interacting Proteins) and DPLPs(Dipeptidyl-Peptidase-Like-Proteins), regulate the gating kinetics, cellsurface expression, and subcellular localization of Kv4.3. How KChIPs and DPLPsbind Kv4.3 and regulate its gating properties remains elusive, due to the lackof high-resolution structures of Kv4.3-KChIP and Kv4.3-DPLP complexes.
Recently, the research team ledby Prof. GUO Jiangtao from Zhejiang University Schoolof Medicine determined four structures of human Kv4.3, namely Kv4.3alone, Kv4.3-KChIP1 complex, Kv4.3-KChIP2 complex, and Kv4.3-KChIP1-DPP6complex. Kv4.3 is in an open state with an activated voltage-sensing domain. Inthe structures of Kv4.3-KChIP1 complex and Kv4.3-KChIP2 complex, the N-terminaldomain and the C-terminal domain of Kv4.3, which are involved in the channelinactivation, are sequestered by KChIP1 or KChIP2, elucidating how KChIP1 andKChIP2 slow the initial fast inactivation and accelerate recovery from inactivationof Kv4.3. In the structure of the Kv4.3-KChIP1-DPP6 complex, the transmembranehelix of DPP6 interacts and stabilizes S1 and S2 in the voltage-sensing domain,likely enhancing the channel’s voltage sensitivity, which can explain why DPLPsare able to modulate Kv4.3 gating by shifting the voltage dependence ofactivation and inactivation toward more negative membrane potentials. Thesestructures provide insights into the complex gating modulation of Kv4.3 bydifferent auxiliary subunits.
Fig.1Structures of Kv4.3 alone, Kv4.3-KChIP1, Kv4.3-KChIP2, and Kv4.3-KChIP1-DPP6complexes.
