ArticleProceedings of the National Academy of Sciences of the United States of America2015
Ack1 is a dopamine transporter endocytic brake that rescues a trafficking-dysregulated ADHD coding variant.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 59 citations in OpenAlex.
- ACK1/TNK2 kinase: molecular mechanisms and emerging cancer therapeutics.Trends in pharmacological sciences · 2025Review
- Regulation of Dopamine Transporter Surface Expression.Advances in neurobiology · 2025Review
- Dopamine transporter endocytic trafficking: Neuronal mechanisms and potential impact on DA-dependent behaviors.Journal of neurochemistry · 2025Review
- Cholesterol modulation of interactions between psychostimulants and dopamine transporters.Advances in pharmacology (San Diego, Calif.) · 2024Article
- The Alkylamine Stimulant 1,3-Dimethylamylamine Exhibits Substrate-Like Regulation of Dopamine Transporter Function and Localization.The Journal of pharmacology and experimental therapeutics · 2023Article
- Review
- Atorvastatin differentially regulates the interactions of cocaine and amphetamine with dopamine transporters.Neuropharmacology · 2023Article
- Integrated regulation of dopaminergic and epigenetic effectors of neuroprotection in Parkinson's disease models.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Presynaptic Gq-coupled receptors drive biphasic dopamine transporter trafficking that modulates dopamine clearance and motor function.The Journal of biological chemistry · 2023Article
- Precise CRISPR-Cas9-mediated mutation of a membrane trafficking domain in theCurrent research in physiology · 2023Article
- Systemic RNA Interference Defective (SID) genes modulate dopaminergic neurodegeneration in C. elegans.PLoS genetics · 2022Article
- Dopaminergic Ric GTPase activity impacts amphetamine sensitivity and sleep quality in a dopamine transporter-dependent manner in Drosophila melanogaster.Molecular psychiatry · 2021Article
- Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease.JCI insight · 2021Article
- Proximity-Dependent Biotinylation to Elucidate the Interactome of TNK2 Nonreceptor Tyrosine Kinase.Journal of proteome research · 2021Article
- Is It Time to Use Modeling of Cellular Transporter Homeostasis to Inform Drug-Drug Interaction Studies: Theoretical Considerations.The AAPS journal · 2021Article
- Functional and Biochemical Consequences of Disease Variants in Neurotransmitter Transporters: A Special Emphasis on Folding and Trafficking Deficits.Pharmacology & therapeutics · 2021Review
- ACK1 is dispensable for development, skin tumor formation, and breast cancer cell proliferation.FEBS open bio · 2021Article
- Article
- Dynamic control of the dopamine transporter in neurotransmission and homeostasis.NPJ Parkinson's disease · 2021Review
- Acetylcholine Receptor Stimulation Activates Protein Kinase C Mediated Internalization of the Dopamine Transporter.Frontiers in cellular neuroscience · 2021Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
The dopamine (DA) transporter (DAT) facilitates high-affinity presynaptic DA reuptake that temporally and spatially constrains DA neurotransmission. Aberrant DAT function is implicated in attention-deficit/hyperactivity disorder and autism spectrum disorder. DAT is a major psychostimulant target, and psychostimulant reward strictly requires binding to DAT. DAT function is acutely modulated by dynamic membrane trafficking at the presynaptic terminal and a PKC-sensitive negative endocytic mechanism, or "endocytic brake," controls DAT plasma membrane stability. However, the molecular basis for the DAT endocytic brake is unknown, and it is unknown whether this braking mechanism is unique to DAT or common to monoamine transporters. Here, we report that the cdc42-activated, nonreceptor tyrosine kinase, Ack1, is a DAT endocytic brake that stabilizes DAT at the plasma membrane and is released in response to PKC activation. Pharmacologic and shRNA-mediated Ack1 silencing enhanced basal DAT internalization and blocked PKC-stimulated DAT internalization, but had no effects on SERT endocytosis. Both cdc42 activation and PKC stimulation converge on Ack1 to control Ack1 activity and DAT endocytic capacity, and Ack1 inactivation is required for stimulated DAT internalization downstream of PKC activation. Moreover, constitutive Ack1 activation is sufficient to rescue the gain-of-function endocytic phenotype exhibited by the ADHD DAT coding variant, R615C. These findings reveal a unique endocytic control switch that is highly specific for DAT. Moreover, the ability to rescue the DAT(R615C) coding variant suggests that manipulating DAT trafficking mechanisms may be a potential therapeutic approach to correct DAT coding variants that exhibit trafficking dysregulation.
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