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Nat Chem Biol. 2014 Jul;10(7):582-589. doi: 10.1038/nchembio.1545. Epub 2014 Jun 1.

PIP2 regulates psychostimulant behaviors through its interaction with a membrane protein.

Author information

1
Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States.
2
Neuroscience Program in Substance Abuse, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States.
3
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States.
4
Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, New York 10065, United States.
5
Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States.
6
Department of Psychiatry, Columbia University College of Physicians & Surgeons, New York, New York 10032, United States.
7
Department of Pharmacology, Columbia University College of Physicians & Surgeons, New York, New York 10032, United States.
8
Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria.
9
HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute of Computational Biomedicine, Weill Cornell Medical College of Cornell University, New York, New York 10065, United States.
#
Contributed equally

Erratum in

Abstract

Phosphatidylinositol (4,5)-bisphosphate (PIP2) regulates the function of ion channels and transporters. Here, we demonstrate that PIP2 directly binds the human dopamine (DA) transporter (hDAT), a key regulator of DA homeostasis and a target of the psychostimulant amphetamine (AMPH). This binding occurs through electrostatic interactions with positively charged hDAT N-terminal residues and is shown to facilitate AMPH-induced, DAT-mediated DA efflux and the psychomotor properties of AMPH. Substitution of these residues with uncharged amino acids reduces hDAT-PIP2 interactions and AMPH-induced DA efflux without altering the hDAT physiological function of DA uptake. We evaluated the significance of this interaction in vivo using locomotion as a behavioral assay in Drosophila melanogaster. Expression of mutated hDAT with reduced PIP2 interaction in Drosophila DA neurons impairs AMPH-induced locomotion without altering basal locomotion. We present what is to our knowledge the first demonstration of how PIP2 interactions with a membrane protein can regulate the behaviors of complex organisms.

PMID:
24880859
PMCID:
PMC4062427
DOI:
10.1038/nchembio.1545
[Indexed for MEDLINE]
Free PMC Article

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