RESUMEN
Regulatory ß-subunits of large conductance calcium- and voltage-activated potassium (BK) channels play an important role in generating functional diversity and control of cell surface expression of the pore forming α-subunits. However, in contrast to α-subunits, the role of reversible post-translational modification of intracellular residues on ß-subunit function is largely unknown. Here we demonstrate that the human ß4-subunit is S-acylated (palmitoylated) on a juxtamembrane cysteine residue (Cys-193) in the intracellular C terminus of the regulatory ß-subunit. ß4-Subunit palmitoylation is important for cell surface expression and endoplasmic reticulum (ER) exit of the ß4-subunit alone. Importantly, palmitoylated ß4-subunits promote the ER exit and surface expression of the pore-forming α-subunit, whereas ß4-subunits that cannot be palmitoylated do not increase ER exit or surface expression of α-subunits. Strikingly, however, this palmitoylation- and ß4-dependent enhancement of α-subunit surface expression was only observed in α-subunits that contain a putative trafficking motif ( REVEDEC) at the very C terminus of the α-subunit. Engineering this trafficking motif to other C-terminal α-subunit splice variants results in α-subunits with reduced surface expression that can be rescued by palmitoylated, but not depalmitoylated, ß4-subunits. Our data reveal a novel mechanism by which palmitoylated ß4-subunit controls surface expression of BK channels through masking of a trafficking motif in the C terminus of the α-subunit. As palmitoylation is dynamic, this mechanism would allow precise control of specific splice variants to the cell surface. Our data provide new insights into how complex interplay between the repertoire of post-transcriptional and post-translational mechanisms controls cell surface expression of BK channels.