Reciprocal Phosphorylation and Palmitoylation Control Dopamine Transporter Kinetics

Moritz, Amy E.; Rastedt, Danielle; Stanislowski, Daniel J.; Shetty, Madhur; Smith, Margaret A.; Vaughan, Roxanne A.; Foster, James D.

doi:10.1074/jbc.m115.667055

Cited by 50 publications

(61 citation statements)

References 65 publications

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“…The acute decreases in the kinetic efficiency of transport with reduced palmitoylation indicates that palmitoylation function to enhance the kinetic capacity of the transporter. Consistent with these findings transport V max of palmitoylation-deficient C580A DAT is strongly reduced relative to the WT protein (Moritz et al , 2015). PMA-induced downregulation is also increased in 2BP-treated and C580A DATs, indicating that the enhanced activity derived from palmitoylation functions to oppose PKC-induced down-regulation (Foster and Vaughan, 2011).…”

Section: Dat Palmitoylation Characteristicssupporting

confidence: 56%

“…Currently there are few specific pharmacological PAT activators or inhibitors, limiting the experimental approaches available for examining functional properties. However, functional consequences of modification can be probed by reducing palmitoylation with the compound 2-bromopalmitate (2BP) a nonspecific irreversible PAT inhibitor (Jennings et al , 2009), or by increasing palmitoylation by overexpression of PAT enzymes (Fukata et al , 2004; Moritz et al , 2015). …”

Section: Protein S-palmitoylationmentioning

confidence: 99%

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Palmitoylation mechanisms in dopamine transporter regulation

Rastedt

Vaughan

Foster

2017

Journal of Chemical Neuroanatomy

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The neurotransmitter dopamine (DA) plays a key role in several biological processes including reward, mood, motor activity and attention. Synaptic DA homeostasis is controlled by the dopamine transporter (DAT) which transports extracellular DA into the presynaptic neuron after release and regulates its availability to receptors. Many neurological disorders such as schizophrenia, bipolar disorder, Parkinson disease and attention-deficit hyperactivity disorder are associated with imbalances in DA homeostasis that may be related to DAT dysfunction. DAT is also a target of psychostimulant and therapeutic drugs that inhibit DA reuptake and lead to elevated dopaminergic neurotransmission. We have recently demonstrated the acute and chronic modulation of DA reuptake activity and DAT stability through S-palmitoylation, the linkage of a 16-carbon palmitate group to cysteine via a thioester bond. This review summarizes the properties and regulation of DAT palmitoylation and describes how it serves to affect various transporter functions. Better understanding of the role of palmitoylation in regulation of DAT function may lead to identification of therapeutic targets for modulation of DA homeostasis in the treatment of dopaminergic disorders.

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Section: Dat Palmitoylation Characteristicssupporting

confidence: 56%

Section: Protein S-palmitoylationmentioning

confidence: 99%

Palmitoylation mechanisms in dopamine transporter regulation

Rastedt

Vaughan

Foster

2017

Journal of Chemical Neuroanatomy

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“…Inhibition of DAT palmitoylation by the palmitoyl acyltransferase inhibitor 2-bromopalmitate in rat striatal synaptosomes led to decreases in the V max of DA uptake independent of changes in DAT surface levels, supporting a role for this modification in trafficking-independent regulation of DAT activity (Foster and Vaughan, 2011). Importantly, activation and inhibition of PKC by PMA/BIM-1 decreased and increased palmitoylation of DAT, respectively, and mutation of the PKC target Ser7 to alanine abolished these effects on palmitoylation (Moritz et al, 2015). Critically, unlike wild-type DAT, this mutant showed no downregulation of uptake in response to PMA when endocytosis was blocked by ConA, suggesting that the trafficking-independent effects of PMA are likely mediated through phosphorylation of S7A, potentially via its role in regulating palmitoylation of DAT.…”

Section: Regulation Of Dopamine Transporter Membranementioning

confidence: 79%

Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters

Bermingham

Blakely

2016

Pharmacol Rev

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“…Phosphorylation of TRPP3 at Thr-39 -Because there have been reports about an interplay between palmitoylation and phosphorylation at a nearby site (37,39,40), we next examined potential phosphorylation sites near Cys-38. Five candidate phosphorylation sites, Thr-34, Thr-39, Ser-41, Ser-42, and Thr-43 are predicted in human TRPP3 by GPS 3.0 program (Fig.…”

Section: -E)mentioning

confidence: 99%

Regulation of TRPP3 Channel Function by N-terminal Domain Palmitoylation and Phosphorylation

Zheng¹,

Yang²,

Beauchamp

et al. 2016

Journal of Biological Chemistry

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Edited by Roger ColbranTransient receptor potential polycystin-3 (TRPP3) is a cation channel activated by calcium and proton and is involved in hedgehog signaling, intestinal development, and sour tasting. How TRPP3 channel function is regulated remains poorly understood. By N-terminal truncation mutations, electrophysiology, and Xenopus oocyte expression, we first identified fragment Asp-21-Ser-42 to be functionally important. We then found that deletion mutant ⌬1-36 (TRPP3 missing fragment Met-1-Arg-36) has a similar function as wild-type TRPP3, whereas ⌬1-38 is functionally dead, suggesting the importance of Val-37 or Cys-38. Further studies found that Cys-38, but not Val-37, is functionally critical. Cys-38 is a predicted site of palmitoylation, and indeed TRPP3 channel activity was inhibited by palmitoylation inhibitor 2-bromopalmitate and rescued by palmitoylation substrate palmitic acid. The TRPP3 N terminus (TRPP3NT, Met-1-Leu-95) localized along the plasma membrane of HEK293 cells but stayed in the cytoplasm with 2-bromopalmitate treatment or C38A mutation, indicating that TRPP3NT anchors to the surface membrane through palmitoylation at Cys-38. By acyl-biotin exchange assays, we showed that TRPP3, but not mutant C38A, is indeed palmitoylated. When putative phosphorylation sites near Cys-38 were mutated to Asp or Glu to mimic phosphorylation, only T39D and T39E reduced TRPP3 function. Furthermore, TRPP3NT displayed double bands in which the upper band was abolished by phosphatase treatment or T39A mutation. However, palmitoylation at Cys-38 and phosphorylation at Thr-39 independently regulated TRPP3 channel function, in contrast to previous reports about correlated palmitoylation with a proximate phosphorylation. Palmitoylation at Cys-38 represents a novel mechanism of functional regulation for TRPP3.

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Reciprocal Phosphorylation and Palmitoylation Control Dopamine Transporter Kinetics

Cited by 50 publications

References 65 publications

Palmitoylation mechanisms in dopamine transporter regulation

Palmitoylation mechanisms in dopamine transporter regulation

Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters

Regulation of TRPP3 Channel Function by N-terminal Domain Palmitoylation and Phosphorylation

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