GSBS Student Publications

Student Author(s)

Deanna M. Navaroli; Luke Gabriel

GSBS Program

Interdisciplinary Graduate Program

Publication Date

2011-09-28

UMMS Affiliation

Department of Psychiatry; Program in Molecular Medicine

Document Type

Article

Disciplines

Life Sciences | Medicine and Health Sciences | Neuroscience and Neurobiology

Abstract

Dopaminergic signaling and plasticity are essential to numerous CNS functions and pathologies, including movement, cognition, and addiction. The amphetamine- and cocaine-sensitive dopamine (DA) transporter (DAT) tightly controls extracellular DA concentrations and half-life. DAT function and surface expression are not static but are dynamically modulated by membrane trafficking. We recently demonstrated that the DAT C terminus encodes a PKC-sensitive internalization signal that also suppresses basal DAT endocytosis. However, the cellular machinery governing regulated DAT trafficking is not well defined. In work presented here, we identified the Ras-like GTPase, Rin (for Ras-like in neurons) (Rit2), as a protein that interacts with the DAT C-terminal endocytic signal. Yeast two-hybrid, GST pull down and FRET studies establish that DAT and Rin directly interact, and colocalization studies reveal that DAT/Rin associations occur primarily in lipid raft microdomains. Coimmunoprecipitations demonstrate that PKC activation regulates Rin association with DAT. Perturbation of Rin function with GTPase mutants and shRNA-mediated Rin knockdown reveals that Rin is critical for PKC-mediated DAT internalization and functional downregulation. These results establish that Rin is a DAT-interacting protein that is required for PKC-regulated DAT trafficking. Moreover, this work suggests that Rin participates in regulated endocytosis.

Keywords

UMCCTS funding

DOI of Published Version

10.1523/JNEUROSCI.2649-11.2011

Source

J Neurosci. 2011 Sep 28;31(39):13758-70. Link to article on publisher's website

Journal/Book/Conference Title

The Journal of neuroscience : the official journal of the Society for Neuroscience

Related Resources

Link to article in PubMed

PubMed ID

21957239

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