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

Hamilton PJ, Belovich AN, Khelashvili G, Saunders C, Erreger K, Javitch JA, Sitte HH, Weinstein H, Matthies HJG, Galli A
Nat Chem Biol. 2014 10 (7): 582-589

PMID: 24880859 · PMCID: PMC4062427 · DOI:10.1038/nchembio.1545

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.

MeSH Terms (17)

Amino Acid Substitution Amphetamine Animals Behavior, Animal Cell Membrane Central Nervous System Stimulants Dopamine Dopamine Plasma Membrane Transport Proteins Drosophila melanogaster Gene Expression Humans Locomotion Models, Molecular Neurons Phosphatidylinositol 4,5-Diphosphate Protein Structure, Tertiary Transgenes

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