Post‐translational palmitoylation of ionotropic glutamate receptors in excitatory synaptic functions

Abstract

In the mammalian CNS, glutamate is the major excitatory neurotransmitter. Ionotropic glutamate receptors (iGluRs) are responsible for the glutamate‐mediated postsynaptic excitation of neurons. Regulation of glutamatergic synapses is critical for higher brain functions including neural communication, memory formation, learning, emotion, and behaviour. Many previous studies have shown that post‐translational protein S‐palmitoylation, the only reversible covalent attachment of lipid to protein, regulates synaptic expression, intracellular localization, and membrane trafficking of iGluRs and their scaffolding proteins in neurons. This modification mechanism is extremely conserved in the vertebrate lineages. The failure of appropriate palmitoylation‐dependent regulation of iGluRs leads to hyperexcitability that reduces the maintenance of network stability, resulting in brain disorders, such as epileptic seizures. This review summarizes advances in the study of palmitoylation of iGluRs, especially AMPA receptors and NMDA receptors, and describes the current understanding of palmitoylation‐dependent regulation of excitatory glutamatergic synapses. LINKED ARTICLES This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.4/issuetoc

Regulatory effects of post-translational modifications on zDHHC S-acyltransferases

“…These S -acylated proteins include soluble signaling proteins, membrane receptors, ion channels, transporters, molecular scaffolds, and chaperones ( 9 ). Functional roles of S -acylation in all the mammalian physiological systems are continually being uncovered, including important roles in synaptic transmission and plasticity ( 10 , 11 ), cardiac electrophysiology ( 12 , 13 ), hormone release and response pathways ( 11 , 14 ), and immune cell function ( 15 ). In addition, links between S -acylation and pathological processes are also emerging, including in viral and bacterial infection ( 16 ), intellectual disability, epilepsy, schizophrenia, Huntington's disease, diabetes, and cancer ( 9 , 17 – 20 ).…”

Neuronal Signaling Involved in Neuronal Polarization and Growth: Lipid Rafts and Phosphorylation

“…Of the major palmitoylated proteins in the adult brain, more than half are transmembrane proteins (Kang et al, 2008 ). Previous work has demonstrated the significance of palmitoylated transmembrane proteins in neurobiology (Vallejo et al, 2017 ; Hayashi, 2020 ); the relationship of palmitoylation to neuronal polarity will be addressed later in this review article.…”

“…recruitment of such transmembrane proteins to lipid rafts (Linder and Deschenes, 2007;Hayashi, 2020). Palmitoylation is thought to modify the membrane trafficking of the target proteins, possibly by changing the curvature of the sorting vesicles carrying these proteins (Ernst et al, 2019).…”

“…This modification also is employed for membrane proteins, although the purpose of palmitoylation of such proteins (which are already membrane-associated) is less apparent. Notably, however, in various cells (including the neuron), palmitoylation increases recruitment of such transmembrane proteins to lipid rafts (Linder and Deschenes, 2007 ; Hayashi, 2020 ). Palmitoylation is thought to modify the membrane trafficking of the target proteins, possibly by changing the curvature of the sorting vesicles carrying these proteins (Ernst et al, 2019 ).…”

From neurotransmission to neuronal disorders

“…Post‐translational modifications of proteins regulate a variety of cellular functions including neurotransmission. Hayashi (2021) discuss how S‐palmitoylation of ionotropic glutamate receptors modulates their expression, scaffolding, membrane trafficking, and cellular localization in neurons. S‐palmitoylation is a reversible covalent attachment of palmitate, the most abundant saturated fatty acid, to the cysteine residues on target proteins via thioester bonds.…”