ASSEMBLY OF VOLTAGE-GATED POTASSIUM CHANNELS - CONSERVED HYDROPHILIC MOTIFS DETERMINE SUBFAMILY-SPECIFIC INTERACTIONS BETWEEN THE ALPHA-SUBUNITS

Voltage-gated potassium (K+) channels are assembled by four identical or homologous alpha-subunits to form a tetrameric complex with a centr al conduction pore for potassium ions. Most of the cloned genes for th e alpha-subunits are classified into four subfamilies: Kv1 (Shaker), K v2 (Shah), Kv3 (Shaw), and Kv4 (Shal). Subfamily-specific assembly of heteromeric K+ channel complexes has been observed in vitro and in viv o, which contributes to the diversity of K+ currents. However, the mol ecular codes that mediate the subfamily-specific association remain un known. To understand the molecular basis of the subfamily-specific ass embly, we tested the protein-protein interactions of different regions of alpha-subunits. We report here that the cytoplasmic NH2-terminal d omains of Kv1, Kv2, Rv3, and Kv4 subfamilies each associate to form ho momultimers. Using the yeast two-hybrid system and eight K+ channel ge nes, two genes (one isolated from rat and one from Drosophila) from ea ch subfamily, we demonstrated that the associations to form heteromult imers by the NH2-terminal domains are strictly subfamily-specific. The se subfamily-specific associations suggest a molecular basis for the s elective formation of heteromultimeric channels in vivo.