Palmitoylation as a Functional Regulator of Neurotransmitter Receptors

Abstract

The majority of neuronal proteins involved in cellular signaling undergo different posttranslational modifications significantly affecting their functions. One of these modifications is a covalent attachment of a 16-C palmitic acid to one or more cysteine residues (S-palmitoylation) within the target protein. Palmitoylation is a reversible modification, and repeated cycles of palmitoylation/depalmitoylation might be critically involved in the regulation of multiple signaling processes. Palmitoylation also represents a common posttranslational modification of the neurotransmitter receptors, including G protein-coupled receptors (GPCRs) and ligand-gated ion channels (LICs). From the functional point of view, palmitoylation affects a wide span of neurotransmitter receptors activities including their trafficking, sorting, stability, residence lifetime at the cell surface, endocytosis, recycling, and synaptic clustering. This review summarizes the current knowledge on the palmitoylation of neurotransmitter receptors and its role in the regulation of receptors functions as well as in the control of different kinds of physiological and pathological behavior.

Full-Length P2X7 Structures Reveal How Palmitoylation Prevents Channel Desensitization

“…Although ion channels have long been known to be regulated by protein palmitoylation either directly or through adaptor proteins, this form of regulation for ion channels most commonly occurs in processes of protein assembly, maturation, trafficking, insertion into the membrane, localization into membrane microdomains, and internalization/recycling (Naumenko and Ponimaskin, 2018;Shipston, 2011Shipston, , 2014. Examples of palmitoylation modulating intrinsic ion channel activity or gating kinetics are less common but do exist (Shipston, 2011(Shipston, , 2014.…”

Role of Palmitoylation of Postsynaptic Proteins in Promoting Synaptic Plasticity

“…A substantial number of receptors for a variety of neurotransmitters are palmitoylated (reviewed in Naumenko and Ponimaskin, 2018). The majority of G protein-coupled receptors contain putative palmitoylation sites (Probst et al, 1992), but palmitoylation was also established for a number of ionotropic, ligand-gated ion channels including AMPAR, NMDAR, kainate receptors (Pickering et al, 1995), the γ 2 -subunit of the γ-aminobutyric acid type A (GABA A ) receptor (Keller et al, 2004; Rathenberg et al, 2004), the α 4 -subunit of the nicotinic acetylcholine receptor (Amici et al, 2012), and the adenosine triphosphate receptor P2X7 (Gonnord et al, 2009).…”

“…In recent years, the contribution of protein palmitoylation to synapse development and synaptic plasticity was elucidated in more detail. The amount of effort invested in this endeavor is witnessed by a great number of review articles discussing various aspects of palmitoylation in the neuronal system (Fukata and Fukata, 2010; Thomas and Huganir, 2013; Fukata et al, 2015; Han et al, 2015; Cho and Park, 2016; Globa and Bamji, 2017; Naumenko and Ponimaskin, 2018; Zaręba-Kozioł et al, 2018). It is indeed the nervous system, in which protein palmitoylation seems to be particularly important.…”

“…It is noteworthy that there is no specific kind of protein nor any cellular function that predestines a protein for palmitoylation. The long lists of neuronal targets for palmitoylation include presynaptic proteins (Prescott et al, 2009), cytosolic proteins like protein kinases (PKAs; Montersino and Thomas, 2015), and scaffold proteins (see below) as well as integral membrane proteins like neurotransmitter receptors (Naumenko and Ponimaskin, 2018) or ion channels (Shipston, 2014).…”

Anthrax toxin requires ZDHHC5-mediated palmitoylation of its surface-processing host enzymes

“…The absence of the palmitate modification of these proteases does not affect the cleavage capacity per se because ZDHHC5 silencing did not prevent processing of the known Furin/PC7 targets E-cadherin and IGF-1R (27, 29). Palmitoylation has been reported to target a variety of substrates to specific membrane subdomains (10, 58), possibly lipid rafts (36). We also find that palmitoylation of Furin/PC7 allows their partitioning into specific membrane domains, consistent with our observation that the GPI-domain–specific PC biosensor is sensitive to ZDHHC5 silencing.…”