These include: specific inhibitors of zDHHCs and thioesterases, conditional knockouts to spatiotemporally control zDHHC expression, and transgenics expressing catalytically inactive zDHHCs and models expressing S-acylationCnull ion channel subunits. both pore-forming and regulatory subunits as well as through control of adapter, signaling, and scaffolding proteins in ion channel complexes. Importantly, cross-talk of S-acylation with other PTMs of both cysteine residues by themselves and neighboring sites of phosphorylation is an emerging concept in the control of ion channel physiology. In this review, I discuss the fundamentals of protein S-acylation and the tools available to investigate ion channel S-acylation. The mechanisms and role of S-acylation in controlling diverse stages of the ion channel life cycle Lixisenatide and its effect on ion channel function are highlighted. Finally, I discuss future goals and difficulties for the field to understand both the mechanistic basis for S-acylation control of ion channels and the functional result and implications for understanding the physiological function of ion channel S-acylation in health and disease. Ion channels are modified by the attachment to the channel protein of a wide array of small signaling molecules. These include phosphate groups (phosphorylation), ubiquitin (ubiquitination), small ubiquitin-like modifier (SUMO) proteins (SUMOylation), and various lipids (lipidation). Such PTMs are critical for controlling the physiological function of ion Lixisenatide channels through regulation of the number of ion channels resident in the (plasma) membrane; their activity, kinetics, and modulation by other PTMs; or their conversation with other proteins. S-acylation is one of a group of covalent lipid modifications (Resh, 2013). However, unlike N-myristoylation and prenylation (which includes farnesylation and geranylgeranylation), S-acylation is usually reversible (Fig. 1). Because of the labile thioester bond, S-acylation thus represents a dynamic lipid modification to spatiotemporally control protein function. The most common form of S-acylation, the attachment of Lixisenatide the C16 lipid palmitate to proteins (referred to as S-palmitoylation), was first described more than 30 years ago in the transmembrane glycoprotein of the vesicular stomatitis computer virus and various mammalian membrane proteins (Schmidt and Schlesinger, 1979; Schlesinger et al., 1980). A decade later, S-acylated ion channelsrodent voltage-gated sodium channels (Schmidt and Catterall, 1987) and the M2 ion channel from your influenza computer Lixisenatide virus (Sugrue et al., 1990)were first characterized. Since then, more than 50 unique ion channel subunits have been experimentally demonstrated to be S-acylated (Furniture 1C3) as have a wide array of structural, signaling, and scaffolding proteins (for reviews observe El-Husseini and Bredt, 2002; Linder and Deschenes, 2007; Fukata and Fukata, 2010; Greaves and Chamberlain, 2011; Resh, 2012). In the last few years, with the cloning of enzymes controlling S-acylation and development of various proteomic tools, we have begun to gain substantial mechanistic and physiological insight into how S-acylation may control multiple facets of the life cycle of ion channels: from their assembly, through their trafficking and regulation at the plasma membrane, to their final degradation (Fig. 2). Open in a separate window Physique 1. Protein S-acylation: a Lixisenatide reversible lipid posttranslational modification of proteins. (A) Major lipid modifications of proteins. S-acylation is usually reversible due to the labile thioester bond between the lipid (typically, but not exclusively, palmitate) and the cysteine amino acid of is target protein. Other lipid modifications result from stable bond formation between either the N-terminal amino acid (amide) or the amino acid side chain in the protein (thioether and oxyester). The zDHHC family of palmitoyl acyltransferases mediates S-acylation with other Trp53 enzyme families controlling other lipid modifications: N-methyltransferase (NMT) controls myristoylation of many proteins such as the src family kinase, Fyn kinase; and amide-linked palmitoylation of the secreted sonic hedgehog protein is usually mediated by Hedgehog acyltransferase (Hhat), a membrane-bound O-acyl transferase (MBOAT) family. Prenyl transferases catalyze farnesyl (farnesyltransferase, FTase) or geranylgeranyl (geranylgeranyl transferase I [GGTase I] and geranylgeranyl transferase II [GGTase II]) in.