A novel nervous system beta subunit that downregulates human large conductance calcium-dependent potassium channels

The pore-forming alpha subunits of many ion channels are associated with au xiliary subunits that influence channel expression, targeting, and function . Several different auxiliary (beta) subunits for large conductance calcium -dependent potassium channels of the Slowpoke family have been reported, bu t none of these beta subunits is expressed extensively in the nervous syste m. We describe here the cloning and functional characterization of a novel Slowpoke beta 4 auxiliary subunit in human and mouse, which exhibits only l imited sequence homology with other beta subunits. This beta 4 subunit coim munoprecipitates with human and mouse Slowpoke. beta 4 is expressed highly in human and monkey brain in a pattern that overlaps strikingly with Slowpo ke alpha subunit, but in contrast to other Slowpoke beta subunits, it is ex pressed little (if at all) outside the nervous system. Also in contrast to other beta subunits, beta 4 downregulates Slowpoke channel activity by shif ting its activation range to more depolarized voltages and slowing its acti vation kinetics. beta 4 may be important for the critical roles played by S lowpoke channels in the regulation of neuronal excitability and neurotransm itter release.