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Phosphatidylinositol (4,5)‐bisphosphate regulates psychostimulant behaviors through its interaction with the dopamine transporter (803.2)
Author(s) -
Hamilton Peter,
Belovich Andrea,
Khelashvili George,
Saunders Christine,
Erreger Kevin,
Javitch Jonathan,
Sitte Harald,
Weinstein Harel,
Matthies Heinrich,
Galli Aurelio
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.803.2
Subject(s) - dopamine transporter , amphetamine , dopamine plasma membrane transport proteins , dopamine , transporter , chemistry , efflux , microbiology and biotechnology , drosophila melanogaster , biochemistry , dopaminergic , neuroscience , biology , gene
Phosphatidylinositol (4,5)‐bisphosphate (PIP2) is known to regulate the function of ion channels and transporters. The human dopamine (DA) transporter (hDAT) is a key regulator of DA homeostasis and a target of the psychostimulant amphetamine (AMPH). AMPH’s addictive properties are mediated, at least in part, through elevation of extracellular DA by inducing DA efflux through the DAT. Thus, the objective of our study is to understand how to precisely manipulate the DAT to prevent DA efflux without altering its physiological function of DA uptake. This understanding is paramount to the development of pharmacological therapies for AMPH abuse. Here, we demonstrate that PIP2 directly binds to the hDAT. 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, for the first time, 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 the first demonstration of how PIP2 interactions with a membrane protein can regulate organismal behaviors, such as locomotion. Grant Funding Source : Supported by DGE0909667 & F31 DA 035535‐01(PJH), P22893(HHS), DA13975(AG), P01 DA12408(AG, HW, JAJ)