A versatile functional interaction between electrically silent K_V subunits and K_V7 potassium channels

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_VS), however, are unable to conduct currents on their own. It has been assumed that these K_VS must obligatorily assemble with subunits from the K_V2 family into heterotetrameric channels, thereby giving rise to currents distinct from those of homomeric K_V2 channels. Herein, we show that K_VS subunits indeed also modulate the activity, biophysical properties and surface expression of recombinant K_V7 isoforms in a subunit-specific manner. Employing co-immunoprecipitation, and proximity labelling, we unveil the spatial coexistence of K_VS and K_V7 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_VS and K_V7 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.