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

Abstract

The pore-forming α subunits of many ion channels are associated with auxiliary subunits that influence channel expression, targeting, and function. Several different auxiliary (β) subunits for large conductance calcium-dependent potassium channels of the Slowpoke family have been reported, but none of these β subunits is expressed extensively in the nervous system. We describe here the cloning and functional characterization of a novel Slowpoke β4 auxiliary subunit in human and mouse, which exhibits only limited sequence homology with other β subunits. This β4 subunit coimmunoprecipitates with human and mouse Slowpoke. β4 is expressed highly in human and monkey brain in a pattern that overlaps strikingly with Slowpoke α subunit, but in contrast to other Slowpoke β subunits, it is expressed little (if at all) outside the nervous system. Also in contrast to other β subunits, β4 downregulates Slowpoke channel activity by shifting its activation range to more depolarized voltages and slowing its activation kinetics. β4 may be important for the critical roles played by Slowpoke channels in the regulation of neuronal excitability and neurotransmitter release.