Abstract Voltage-gated K + (K V ) channels govern K + ion flux across cell membranes in response to changes in membrane potential. They are formed by the assembly of four subunits, typically from the same family. Electrically silent K V channels (K V S), however, are unable to conduct currents on their own. It has been assumed that these K V S must obligatorily assemble with subunits from the K V 2 family into heterotetrameric channels, thereby giving rise to currents distinct from those of homomeric K V 2 channels. Herein, we show that K V S subunits indeed also modulate the activity, biophysical properties and surface expression of recombinant K V 7 isoforms in a subunit-specific manner. Employing co-immunoprecipitation, and proximity labelling, we unveil the spatial coexistence of K V S and K V 7 within a single protein complex. Electrophysiological experiments further indicate functional interaction and probably heterotetramer formation. Finally, single-cell transcriptomic analyses identify native cell types in which this K V S and K V 7 interaction may occur. Our findings demonstrate that K V cross-family interaction is much more versatile than previously thought—possibly serving nature to shape potassium conductance to the needs of individual cell types.
