Beyond the Alpha Subunit: Pharmacological Modulation of Kv4.2 Channels by Ancillary Proteins

Figure 1. Schematic representation of the Kv4.2 architecture. (A) Membrane topology of a single Kv4.2 subunit, indicating the voltage-sensing domain (S1–S4) and the pore-forming region (S5–S6). (B) Tetrameric organization of the Kv4.2 subunits forming the functional channel around a central pore. (C) Crystal structure of the tetrameric assembly of the Kv4.2 channel (accession code 7F0J) in front view. (D) Top view of the same structure. In panels (B–D), the transmembrane segments are displayed using the same color code defined in (A). All three-dimensional structures shown throughout the manuscript were rendered using ChimeraX (San Francisco, CA, USA; v. 1.10.dev202501180816).

Figure 2. Three-dimensional structures of KChIP proteins and their association with Kv4.2 channels. (A) Crystal structures of the four KChIP isoforms illustrating differences in their overall fold: KChIP1 (PDB ID: 1S1E), KChIP2 (PDB ID: 7UKH), KChIP3 (PDB ID: 2JUL), and KChIP4 (PDB ID: 3DD4). (B) Three-dimensional structure of the octameric complex formed by the tetrameric Kv4.2 channel associated with four KChIP1 subunits (PDB ID: 7E84), showing the stoichiometric binding of four auxiliary KChIP1 proteins with the cytoplasmic domains of each Kv4.2 channel-forming subunit.

Figure 3. Three-dimensional structures of DPP6S and DPP10 and their association with Kv4.2 channels. (A) Crystal structures of the auxiliary subunits DPP6S (PDB ID: 1XFD) and DPP10 (PDB ID: 4WJL) are shown individually to illustrate their three-dimensional architecture. (B) Left, structural superposition of DPP6S (blue) and DPP10 (yellow); right, conserved residues mapped onto the structures using a color scale in which conserved positions are shown in purple and variable positions in blue. (C) Three-dimensional structure of the Kv4.2 channel in complex with DPP6S (PDB ID: 7E8B), illustrating the association of this auxiliary subunit with the tetrameric Kv4.2 channel.

Figure 4. Structural organization of the Kv4.2–KChIP1–DPP6S macromolecular complex. (A) Three-dimensional structure of the full heteromultimeric complex composed of the tetrameric Kv4.2 channel associated with four KChIP1 and four DPP6S auxiliary subunits, forming a 12-subunit assembly (PDB ID: 7E8H). (B) Simplified representation of the same complex showing two Kv4.2 α-subunits together with two KChIP1 and two DPP6S subunits to facilitate visualization of the spatial arrangement and interactions among the channel and its auxiliary subunits.