Palmitoylation regulates norepinephrine transporter trafficking and expression and is potentially involved in the pathogenesis of postural orthostatic tachycardia syndrome (original) (raw)
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bioRxiv (Cold Spring Harbor Laboratory), 2023
In the central nervous system, serotonergic signaling modulates sleep, mood, and cognitive control. During neuronal transmission, the synaptic concentration of serotonin is tightly controlled in a spatial and temporal manner by the serotonin transporter (SERT). Dysregulation of serotonergic signaling is implicated in the pathogenesis of major-depressive, obsessive-compulsive, and autism-spectrum disorders, which makes SERT a primary target for prescription therapeutics, most notably selective-serotonin reuptake inhibitors (SSRIs). Spalmitoylation is an increasingly recognized dynamic post-translational modification, regulating protein kinetics, trafficking, and localization patterns upon physiologic/cellular stimuli. In this study, we reveal that human SERTs are a target for palmitoylation, and using the irreversible palmitoyl acyl-transferase inhibitor, 2-bromopalmitate (2BP) we have identified several associated functions. Using a lower dose of 2BP in shorter time frames, inhibition of palmitoylation was associated with reductions in SERT Vmax, without changes in Km or surface expression. With higher doses of 2BP for longer time intervals, inhibition of palmitoylation was consistent with the loss of cell surface and total SERT protein, suggesting palmitoylation is an important mechanism in regulating SERT trafficking and maintenance of SERT protein through biogenic or anti-degradative processes. Additionally, we have identified that treatment with the SSRI escitalopram decreases SERT palmitoylation analogous to 2BP, reducing SERT surface expression and transport capacity. Ultimately, these results reveal palmitoylation is a major regulatory mechanism for SERT kinetics and trafficking and may be the mechanism responsible for escitalopram-induced internalization and loss of total SERT protein.
PLOS Computational Biology, 2015
Palmitoylation involves the reversible posttranslational addition of palmitate to cysteines and promotes membrane binding and subcellular localization. Recent advancements in the detection and identification of palmitoylated proteins have led to multiple palmitoylation proteomics studies but these datasets are contained within large supplemental tables, making downstream analysis and data mining time-consuming and difficult. Consequently, we curated the data from 15 palmitoylation proteomics studies into one compendium containing 1,838 genes encoding palmitoylated proteins; representing approximately 10% of the genome. Enrichment analysis revealed highly significant enrichments for Gene Ontology biological processes, pathway maps, and process networks related to the nervous system. Strikingly, 41% of synaptic genes encode a palmitoylated protein in the compendium. The top disease associations included cancers and diseases and disorders of the nervous system, with Schizophrenia, HD, and pancreatic ductal carcinoma among the top five, suggesting that aberrant palmitoylation may play a pivotal role in the balance of cell death and survival. This compendium provides a much-needed resource for cell biologists and the palmitoylation field, providing new perspectives for cancer and neurodegeneration.
The Dynamic Role of Palmitoylation In Signal Transduction
Trends in biochemical sciences, 1995
Guanine nucleotide binding p:otein (G protein)4inked receptors, the a-subunits of heterotdmedc G proteins and members of the Src family of nonreceptor tyrosine kinases are among many polypeptides that are posttransmationally modified by the addition of palmitate, a mong-chain fatty acid. Attachment of pNmitate to these protein3 is dynamic and may be regulated by their activation. The presence of palmitate appears to pJay a key role in the membrane localization of either the entire polypeptide or parts of it, and may regugate the interactions of these polypeptides with other proteins. ~E~PJ~I'~ OF ,~l~oW'l~. +4P+h LIFE LIFE. ~'~ ~IJTrLE INT~£CT" "/~ O)tR C[41.TkR'P.. ~XEP.cI~.5,/~FTe~ ~ pe,~, THe. PH/~Pf g~'me~s 7He [ Se~lj t~S IT £F.comes ~ST ¢(k~4S, pX..~ ~LCeNjT~ ~ ~Tm~ 7 HIIq SELF. YeM~ t~lk'Nce ~hY No'r
Palmitoylation and the trafficking of peripheral membrane proteins
Biochemical Society Transactions, 2013
Palmitoylation, the attachment of palmitate and other fatty acids on to cysteine residues, is a common post-translational modification of both integral and peripheral membrane proteins. Dynamic palmitoylation controls the intracellular distribution of peripheral membrane proteins by regulating membrane-cytosol exchange and/or by modifying the flux of the proteins through vesicular transport systems.