There are at least five subfamilies of Shaker-like K+ channels. The diverse functions of K+ channels are thought to be further modulated by hydrophilic β subunits. Here we report that Kvβ1 inactivates RCK4 and Shaker B K+ channels of the Kv1 subfamily, but not Shal2 of the Kv4 subfamily. This correlates the subfamily-specific binding of Kvβ1 to the cytoplasmic N-terminal domains of Kv1 α subunits. We map the Kvβ1-binding site to a region overlapping NAB(Kv1), a domain that specifies different Kv1 α subunits to form heterotetramers. Using chimeric α subunits, we demonstrate that NAB(Kv1) is essential for the Kvβ1-mediated inactivation. These results suggest that Kvβ1 modulates a subset of K+ channels through the specific assembly of α-β complexes and reveal the dual function of the NAB domain in mediating the assembly of both α-α and α-β complexes.
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