The neuronal Kv4 channel complex

Abstract

Kv4 channel complexes mediate the neuronal somatodendritic A-type K(+) current (I(SA)), which plays pivotal roles in dendritic signal integration. These complexes are composed of pore-forming voltage-gated alpha-subunits (Shal/Kv4) and at least two classes of auxiliary beta-subunits: KChIPs (K(+)-Channel-Interacting-Proteins) and DPLPs (Dipeptidyl-Peptidase-Like-Proteins). Here, we review our investigations of Kv4 gating mechanisms and functional remodeling by specific auxiliary beta-subunits. Namely, we have concluded that: (1) the Kv4 channel complex employs novel alternative mechanisms of closed-state inactivation; (2) the intracellular Zn(2+) site in the T1 domain undergoes a conformational change tightly coupled to voltage-dependent gating and is targeted by nitrosative modulation; and (3) discrete and specific interactions mediate the effects of KChIPs and DPLPs on activation, inactivation and permeation of Kv4 channels. These studies are shedding new light on the molecular bases of I(SA) function and regulation.

Fig. 1

Structural model of the Kv4 channel complex. This model combines the crystal structures of the DPPX dimer (blue-green, extracellular C-terminal domains only), Kv 1.2 tetramer (blue and red, VSD and PD domains, respectively; S4 and S4S5 linker is light blue) and the T1-KChlP-1 octameric complexes (green and orange, T1 and KChlP-1, respectively); and assumes an overall dodecameric stoichiometry) The dotted line represents the putative location of the DPPX transmembrane segment and intracellular N-terminus. Note that KChlP-1 sequesters and immobilizes the N-terminus of the Kv4 channel (Note: For interpretation of the references to color in this figure legend, the reader is referred to the online version of this article)

Fig. 2

Stereo view of the interfacial Zn²⁺ binding site in the T1 domain of the Kv4.1 channel. A stick representation of the coordinating residues is shown. C131, C132 and H104 are from the same subunit, and C110 is from the neighboring subunit. The blue sphere represents a Zn²⁺ ion in the binding site. Although the isolated T1 domain oligomer is typically Zn²⁺-bound, the T1 domain in the intact Kv4.1 channel appears to be Zn²⁺-free or partially liganded (see text) (Note: For interpretation of the references to color in this figure legend, the reader is referred to the online version of this article)