Palmitoylation by Multiple DHHC Enzymes Enhances Dopamine Transporter Function and Stability
| Autor: | Daniel J. Stanislowski, Amy E. Moritz, James D. Foster, Danielle E. Bolland, Roxanne A. Vaughan |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Physiology
Dopamine Lipoylation Cognitive Neuroscience Protein degradation Synaptic Transmission Biochemistry Article Reuptake 03 medical and health sciences 0302 clinical medicine Palmitoylation Animals 030304 developmental biology Dopamine transporter chemistry.chemical_classification Dopamine Plasma Membrane Transport Proteins 0303 health sciences biology Protein Stability Chemistry Transporter Cell Biology General Medicine Rats Cell biology Enzyme Acyltransferases biology.protein 030217 neurology & neurosurgery Function (biology) |
| Zdroj: | ACS Chem Neurosci |
| ISSN: | 1948-7193 |
| DOI: | 10.1021/acschemneuro.8b00558 |
| Popis: | The dopamine transporter (DAT) is a plasma membrane protein that mediates the reuptake of extracellular dopamine (DA) and controls the spatiotemporal dynamics of dopaminergic neurotransmission. The transporter is subject to fine control that tailors clearance of transmitter to physiological demands, and dysregulation of reuptake induced by psychostimulant drugs, transporter polymorphisms, and signaling defects may impact transmitter tone in disease states. We previously demonstrated that DAT undergoes complex regulation by palmitoylation, with acute inhibition of the modification leading to rapid reduction of transport activity, and sustained inhibition of the modification leading to transporter degradation and reduced expression. Here, to examine mechanisms and outcomes related to increased modification, we co-expressed DAT with palmitoyl acyltransferases (PATs), also known as DHHC enzymes, which catalyze palmitate addition to proteins. Of twelve PATs tested, DAT palmitoylation was stimulated by DHHC2, DHHC3, DHHC8, DHHC15, and DHHC17, with others having no effect. Increased modification was localized to previously identified palmitoylation site Cys580 and resulted in upregulation of transport kinetics and elevated transporter expression mediated by reduced degradation. These findings confirm palmitoylation as a regulator of multiple DAT properties crucial for appropriate DA homeostasis and identify several potential PAT pathways linked to these effects. Defects in palmitoylation processes thus represent possible mechanisms of transport imbalances in DA disorders. |
| Databáze: | OpenAIRE |
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