Palmitoylation of the β4-subunit regulates surface expression of large conductance calcium-activated potassium channel splice variants

J Biol Chem. 2013 May 3;288(18):13136-44. doi: 10.1074/jbc.M113.461830. Epub 2013 Mar 16.


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 α-subunits. However, in contrast to α-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, palmitoylated β4-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 palmitoylation- and β4-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, 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 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.

Keywords: Ion Channels; Membrane Transport; Potassium Channels; Protein Palmitoylation; S-Acylation; Signal Transduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism*
  • Gene Expression Regulation / physiology*
  • HEK293 Cells
  • Humans
  • Large-Conductance Calcium-Activated Potassium Channels / biosynthesis*
  • Large-Conductance Calcium-Activated Potassium Channels / genetics
  • Lipoylation / physiology*
  • Protein Isoforms / biosynthesis
  • Protein Isoforms / genetics
  • Protein Processing, Post-Translational / physiology*
  • Protein Subunits / genetics
  • Protein Subunits / metabolism*
  • Protein Transport / physiology


  • Large-Conductance Calcium-Activated Potassium Channels
  • Protein Isoforms
  • Protein Subunits