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Review
. 2014 Aug 5:5:281.
doi: 10.3389/fphys.2014.00281. eCollection 2014.

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

Michael J Shipston  1
Affiliations
Review

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

Michael J Shipston. Front Physiol. .

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.

Keywords: KCNMA1; KCNMB4; MaxiK channel; Slo1; acylation; palmitoylation; phosphorylation; trafficking.

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Figures

Figure 1
Figure 1
S-acylation of BK channels. (A) Schematic of reversible enzymatic regulation S-acylation of proteins. Addition of lipid (typically palmitate) to cysteine residues in target proteins via a thioester bond is catalyzed by a family of palmitoyl acyltransferases (zDHHCs). Removal of lipid results from the action of acylthioesterases. (B) S-acylation controls multiple steps in the lifecycle of BK channels including control of forward trafficking, surface expression and intrinsic channel properties and modulation by other signaling pathways. (C) Schematic of the pore-forming α-subunit of the BK channel encoded by the single KCNMA1 gene. α-subunits are S-acylated at two distinct sites by distinct acyl transferase (zDHHCs): the conserved intracellular S0-S1 loop and the alternatively spliced STREX insert in the C-terminal linker between the two regulator of potassium conductance (RCK) domains. S-acylation of the S0-S1 loop controls surface trafficking of the channel whereas S-acylation of the STREX insert determines channel activity and regulation by AGC-family protein kinases. (D) Schematic of the regulatory β4-subunit encoded by the KCNMB4 gene. The β4-subunit is S-acylated at a single cysteine juxtaposed to the second transmembrane domain in the intracellular C-terminus. S-acylation of the β4-subunit controls surface expression of distinct BK channel α-subunit splice variants.
Figure 2
Figure 2
S-acylation of the α-subunit controls distinct properties of BK channels. Model schema for regulation of STREX variant α-subunits by S-acylation and AGC-family kinases. The STREX variant of the BK channel can be S-acylated at two distinct sites: (i) the S0-S1 loop allowing the loop to associate with the plasma membrane and is important in controlling surface delivery of the BK channel; (ii) in the alternatively spliced STREX insert that allows the cytosolic STREX domain to interact with the plasma membrane. S-acylation of the STREX insert determines STREX channel regulation by AGC-family protein kinase dependent phosphorylation. Protein kinase A (PKA)-dependent phosphorylation of S636 in the STREX insert (purple hexagon), that is immediately upstream of the S-acylated cysteine residues, results in dissociation of the STREX domain from the plasma membrane and inhibition of STREX channel activity. In contrast, when STREX is S-acylated, protein kinase C (PKC) has no effect on channel activity even though phosphorylation of the PKC-consensus sites (S700 and S1156), that are downstream of the STREX insert, result in channel inhibition in channels lacking the STREX insert (e.g., ZERO variant). Thus, the S-acylated STREX insert prevents PKC-mediated inhibition in STREX channels. However, deacylation of the STREX insert, or PKA mediated dissociation of the STREX domain from the plasma membrane, now allows phosphorylation of the S700 PKC-site (S700, gray triangle) that, in conjunction with the C-terminal PKC site S1156, confers PKC-dependent inhibition of STREX channels. Thus, the S-acylation of STREX serves as a switch to determine STREX BK channel regulation by either PKA or PKC. PKG- mediated activation of STREX channels, dependent on phosphorylation of other C-terminal serine residues, is not controlled by STREX insert S-acylation. In combination with control of S0-S1 loop S-acylation channels with distinct surface expression and regulation by AGC-kinases can be generated thus expanding BK channel physiological diversity. For example, channels that are S-acylated at both the S0-S1 loop and STREX insert (center top) would be predicted to have high surface expression and inhibited by PKA. Channels de-acylated at only the S0-S1 loop would have low surface expression but inhibited by PKA (bottom left) whereas channels S-acylated at only the STREX insert would have high surface expression and now inhibited by PKC, but not PKA (bottom right).
Figure 3
Figure 3
Does S-acylation control multiple components of the BK channel signaling complex? Schematic illustrating exemplar proteins that have previously been reported to assembly within a multimolecular complex with the BK channel pore forming α-subunit and are strongly predicted, or have been previously shown, to be S-acylated in cells. The functional consequence of S-acylation, except for the β4-regulatory subunit, of these components on BK channel function is not yet known. Proteins include: additional accessory subunits of the BK channels such as the γ3 subunit LRRC55; G-protein coupled receptors such as the thromboxane A2 (TXA2R) and β2-adrenergic (β2AR) receptors; adapter and scaffolding proteins such as PSD-95, AKAP79/150, caveolin and ANKRA; structural and cytoskeletal proteins such as tubulin and signaling proteins such as the AMP-activated serine/threonine protein kinase (AMPK), the tyrosine kinase, HCK and the serine/threonine protein phosphatase PP1.
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