β Subunits promote K⁺ channel surface expression through effects early in biosynthesis

Voltage-gated K⁺ channels are protein complexes composed of ion- conducting integral membrane subunits and cytoplasmic β subunits. Here, we show that, in transfected mammalian cells, the predominant β subunit isoform in brain, Kvβ2, associates with the Kv1.2 α subunit early in channel biosynthesis and that Kvβ2 exerts multiple chaperone-like effects on associated Kv1.2 including promotion of cotranslational N-linked glycosylation of the nascent Kv1.2 polypeptide, increased stability of Kvβ2/Kv1.2 complexes, and increased efficiency of cell surface expression of Kv1.2. Taken together, these results indicate that while some cytoplasmic K⁺ channel β subunits affect the inactivation kinetics of α subunits, a more general, and perhaps more fundamental, role is to mediate the biosynthetic maturation and surface expression of voltage-gated K⁺ channel complexes. These findings provide a molecular basis for recent genetic studies indicating that β subunits are key determinants of neuronal excitability.