PIP2 regulates psychostimulant behaviors through its interaction with a membrane protein

Academic Article

Abstract

  • Phosphatidylinositol (4,5)-bisphosphate (PIP2) regulates the function of ion channels and transporters. Here, we demonstrate that PIP 2 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. © 2014 Nature America, Inc.
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    Digital Object Identifier (doi)

    Author List

  • Hamilton PJ; Belovich AN; Khelashvili G; Saunders C; Erreger K; Javitch JA; Sitte HH; Weinstein H; Matthies HJG; Galli A
  • Start Page

  • 582
  • End Page

  • 589
  • Volume

  • 10
  • Issue

  • 7