S-acylation dependent post-translational cross-talk regulates large conductance calcium- and voltage- activated potassium (BK) channels.

Michael J Shipston

doi:10.3389/fphys.2014.00281

Abstract

Mechanisms that control surface expression and/or activity of large conductance calcium-activated potassium (BK) channels are important determinants of their (patho)physiological function. Indeed, BK channel dysfunction is associated with major human disorders ranging from epilepsy to hypertension and obesity. S-acylation (S-palmitoylation) represents a major reversible, post-translational modification controlling the properties and function of many proteins including ion channels. Recent evidence reveals that both pore-forming and regulatory subunits of BK channels are S-acylated and control channel trafficking and regulation by AGC-family protein kinases. The pore-forming α-subunit is S-acylated at two distinct sites within the N- and C-terminus, each site being regulated by different palmitoyl acyl transferases (zDHHCs) and acyl thioesterases (APTs). S-acylation of the N-terminus controls channel trafficking and surface expression whereas S-acylation of the C-terminal domain determines regulation of channel activity by AGC-family protein kinases. S-acylation of the regulatory β4-subunit controls ER exit and surface expression of BK channels but does not affect ion channel kinetics at the plasma membrane. Furthermore, a significant number of previously identified BK-channel interacting proteins have been shown, or are predicted to be, S-acylated. Thus, the BK channel multi-molecular signaling complex may be dynamically regulated by this fundamental post-translational modification and thus S-acylation likely represents an important determinant of BK channel physiology in health and disease.

Highlights

The pore-forming α-subunits of large conductance calcium- and voltage- activated potassium (BK) channels are encoded by only a single gene, KCNMA1, yet these channels display considerable functional diversity to control an eclectic array of physiological processes in distinct cells and systems of the body (Salkoff et al, 2006; Contreras et al, 2013)
The zDHHCs that control S0-S1 loop or stress-regulated exon (STREX) insert S-acylation are expressed at either the ER, Golgi or plasma membrane suggesting that the pore-forming α-subunits may be regulated at multiple sites in the trafficking pathways to the plasma membrane
Dissociation of the STREX domain from the plasma membrane via either de-acylation per se or prior protein kinase (PKA)-mediated phosphorylation of the STREX insert at the PKA site S636, would gate the ability of STREX variant channels to be inhibited by protein kinase C (PKC) (Figure 2)

Summary

Introduction

The pore-forming α-subunits of large conductance calcium- and voltage- activated potassium (BK) channels are encoded by only a single gene, KCNMA1, yet these channels display considerable functional diversity to control an eclectic array of physiological processes in distinct cells and systems of the body (Salkoff et al, 2006; Contreras et al, 2013). The zDHHCs that control S0-S1 loop or STREX insert S-acylation are expressed at either the ER, Golgi or plasma membrane suggesting that the pore-forming α-subunits may be regulated at multiple sites in the trafficking pathways to the plasma membrane.

Results

Conclusion