Palmitoylation of the β4-Subunit Regulates Surface Expression of Large Conductance Calcium-activated Potassium Channel Splice Variants.

Regulatory β-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 β-subunits. However, in contrast to β-subunits, the role of reversible post-translational modification of intracellular residues on β-subunit function is largely unknown. Here we demonstrate that the human β4-subunit is S-acylated (palmitoylated) on a juxtamembrane cysteine residue (Cys-193) in the intracellular C terminus of the regulatory β-subunit. β4-Subunit palmitoylation is important for cell surface expression and endoplasmic reticulum (ER) exit of the β4-subunit alone. Importantly, palmitoylatedβ4-subunits promote the ER exit and surface expression of the pore-forming α-subunit, whereas β4-subunits that cannot be palmitoylated do not increase ER exit or surface expression of α-subunits. Strikingly, however, this palmitoylationand β4-dependent enhancement of β-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 β-subunit splice variants results in β-subunits with reduced surface expression that can be rescued by palmitoylated, but not depalmitoylated, β4-subunits. Our data reveal a novel mechanism by which palmitoylated β4-subunit controls surface expression of BK channels through masking of a trafficking motif in the C terminus of the β-subunit. As palmitoylation is dynamic, this mechanism would allow precise control of specific splice variants to the cell surface. Ourdata provide new insights into how complex interplay between the repertoire of post-transcriptional and post-translational mechanisms controls cell surface expression of BK channels. [ABSTRACT FROM AUTHOR]