GSBS Student Publications

Student Author(s)

Sijia Wu

GSBS Program

Neuroscience

UMMS Affiliation

Brudnick Neuropsychiatric Research Institute; Biomedical Imaging Group, Program in Molecular Medicine

Date

12-15-2015

Document Type

Article

Disciplines

Molecular and Cellular Neuroscience

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.

Rights and Permissions

Citation: Proc Natl Acad Sci U S A. 2015 Dec 15;112(50):15480-5. doi: 10.1073/pnas.1512957112. Epub 2015 Nov 30. Link to article on publisher's site

Comments

Publisher's PDF will be posted as allowed by publisher's author rights policy at http://www.pnas.org/site/aboutpnas/rightpermfaq.xhtml

Related Resources

Link to Article in PubMed

Keywords

ADHD, dopamine, membrane trafficking, reuptake, tyrosine kinase

Journal Title

Proceedings of the National Academy of Sciences of the United States of America

PubMed ID

26621748

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