Evolutionary acquisition and divergence of vertebrate HCN2 palmitoylation

2020

British J Pharmacology

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

Section: Ampa Receptors In Excitatory Synapsesmentioning

confidence: 99%

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

2020

British J Pharmacology

“…Similarly, vertebrate-specific conservations of palmitoylation sites are also observed in other ion channels and neurotransmitter receptors (Borroni et al, 2016 ), such as HCN2 ( h yperpolarization-activated c yclic n ucleotide-gated channel 2) orthologs (Itoh et al, 2017 ), a water channel AQP4 ( aq ua p orin family protein 4) orthologs (Hayashi, 2017 ), and serotonin (chemically known as 5-hydroxytryptamine, 5-HT) receptors 5-HT 1A , 5-HT 4 , 5-HT 7 receptor orthologs (Kaizuka and Hayashi, 2018 ).…”

Section: Evolutionary Acquisition and Conservation Of Synaptic Palmitoylation In The Vertebrate Lineagementioning

confidence: 87%

Evolutionarily Established Palmitoylation-Dependent Regulatory Mechanisms of the Vertebrate Glutamatergic Synapse and Diseases Caused by Their Disruption

2021

Front. Mol. Neurosci.

Glutamate is the major excitatory neurotransmitter in the vertebrate brain and various modifications have been established in the glutamatergic synapses. Generally, many neuronal receptors and ion channels are regulated by S-palmitoylation, a reversible post-translational protein modification. Genome sequence databases show the evolutionary acquisition and conservation concerning vertebrate-specific palmitoylation of synaptic proteins including glutamate receptors. Moreover, palmitoylation of some glutamate receptor-binding proteins is subsequently acquired only in some mammalian lineages. Recent progress in genome studies has revealed that some palmitoylation-catalyzing enzymes are the causative genes of neuropsychiatric disorders. In this review, I will summarize the evolutionary development of palmitoylation-dependent regulation of glutamatergic synapses and their dysfunctions which are caused by the disruption of palmitoylation mechanism.

Conservation and phylogenetic stepwise changes of aquaporin (AQP) 4 palmitoylation in vertebrate evolution

2017

Neurotransmitter

The aquaporin (AQP) family channels control water transport across cell membranes in various organs of mammals. Among 13 AQP family subtypes (AQP0-12), AQP4 is predominantly expressed in the central nervous system. Previous studies revealed that AQP4M1 full-length splice variant is specifically palmitoylated at two cysteine residues (Cys13 and Cys17) in its N-terminus and the palmitoylation of these sites regulates the supramolecular assembly of AQP4 isoforms on the membrane. Here, I further focused on conservation of these palmitoylation sites found in animal AQP4 orthologs. Analysis of sequence databases provides an insight into phylogenetic stepwise changes of AQP4 palmitoylation motifs in vertebrate lineages. AQP4 palmitoylation mechanism itself has been almost completely conserved throughout vertebrate species in spite of the divergence of AQP4 full-length amino acid sequences during molecular evolution. My findings indicate that dynamic regulation of AQP4 made possible by reversible post-translational protein palmitoylation may be critical for the specific refined functions of water transport in the vertebrate central nervous system.