Palmitoylation of Voltage-Gated Ion Channels

Abstract

Protein lipidation is one of the most common forms of posttranslational modification. This alteration couples different lipids, such as fatty acids, phospho- and glycolipids and sterols, to cellular proteins. Lipidation regulates different aspects of the protein’s physiology, including structure, stability and affinity for cellular membranes and protein–protein interactions. In this scenario, palmitoylation is the addition of long saturated fatty acid chains to amino acid residues of the proteins. The enzymes responsible for this modification are acyltransferases and thioesterases, which control the protein’s behavior by performing a series of acylation and deacylation cycles. These enzymes target a broad repertoire of substrates, including ion channels. Thus, protein palmitoylation exhibits a pleiotropic role by differential modulation of the trafficking, spatial organization and electrophysiological properties of ion channels. Considering voltage-gated ion channels (VGICs), dysregulation of lipidation of both the channels and the associated ancillary subunits correlates with the development of various diseases, such as cancer or mental disorders. Therefore, a major role for protein palmitoylation is currently emerging, affecting not only the dynamism and differential regulation of a moiety of cellular proteins but also linking to human health. Therefore, palmitoylation of VGIC, as well as related enzymes, constitutes a novel pharmacological tool for drug development to target related pathologies.

Protein lipidation in health and disease: molecular basis, physiological function and pathological implication

“…Studies have shown that S-palmitoylation can influence the function of cardiac myocytes by regulating ion channels and signal transduction. 136 The important role of S-palmitoylation regulation in ion channel homeostasis and excitation-contraction coupling of cardiac myocytes has been discussed in detail in previous reviews. 136,137 Using the S-palmitoylation of voltage-gated sodium channels (NaVs) as an example, we will briefly discuss its influence on cardiac electrical activity and its implications in heart diseases, highlighting the role of S-palmitoylation in maintaining cardiac homeostasis.…”

“…136 The important role of S-palmitoylation regulation in ion channel homeostasis and excitation-contraction coupling of cardiac myocytes has been discussed in detail in previous reviews. 136,137 Using the S-palmitoylation of voltage-gated sodium channels (NaVs) as an example, we will briefly discuss its influence on cardiac electrical activity and its implications in heart diseases, highlighting the role of S-palmitoylation in maintaining cardiac homeostasis. Nav tightly controls the generation and propagation of sodium-dependent action potentials.…”

“…Nav tightly controls the generation and propagation of sodium-dependent action potentials. 136 As a heterotrimeric protein, S-palmitoylation often occurs in the early stages of Nav channel biosynthesis and induces different outcomes by palmitoylating cysteine sites in different regions. 136 For example, the four palmitoylation sites of Nav1.5 are located between structural domains II and III, and S-palmitoylation may modulate the movement of the domain III voltage sensor and channel availability.…”

SIRT6’s function in controlling the metabolism of lipids and glucose in diabetic nephropathy

“…Fatty acylation of lysine is a novel mechanism that regulates protein secretion ( 75 ). Palmitoylation affects cellular protein dynamics and differential regulation ( 76 ). Myristoylation affects plasma targeting, subcellular tracking, and protein localization ( 77 ).…”

S-acylation of Ca2+ transport proteins: molecular basis and functional consequences

“…These Ca 2+ handling proteins are susceptible to a range of post-translational modifications (PTMs) that significantly influence their operational characteristics, activity levels, degradation pathways, subcellular localization, and interactions with other cellular components. These intricate modifications encompass oxidative and reductive modifications, glycosylation, ubiquitination, and acylation [ 6–8 ]. Here, we summarize recent studies reporting the S-acylation of Ca 2+ transporters, detailing the biochemical assays used, the residues and enzymes identified, and the functional consequence of this PTM for calcium fluxes and cellular functions.…”