Functional mechanisms of neurotransmitter transporters regulated by lipid-protein interactions of their terminal loops

Biochim Biophys Acta. 2015 Sep;1848(9):1765-74. doi: 10.1016/j.bbamem.2015.03.025. Epub 2015 Apr 4.


The physiological functions of neurotransmitter:sodium symporters (NSS) in reuptake of neurotransmitters from the synapse into the presynaptic nerve have been shown to be complemented by their involvement, together with non-plasma membrane neurotransmitter transporters, in the reverse transport of substrate (efflux) in response to psychostimulants. Recent experimental evidence implicates highly anionic phosphatidylinositol 4,5-biphosphate (PIP(2)) lipids in such functions of the serotonin (SERT) and dopamine (DAT) transporters. Thus, for both SERT and DAT, neurotransmitter efflux has been shown to be strongly regulated by the presence of PIP(2) lipids in the plasma membrane, and the electrostatic interaction of the N-terminal region of DAT with the negatively charged PIP(2) lipids. We examine the experimentally established phenotypes in a structural context obtained from computational modeling based on recent crystallographic data. The results are shown to set the stage for a mechanistic understanding of physiological actions of neurotransmitter transporters in the NSS family of membrane proteins. This article is part of a Special Issue entitled: Lipid-protein interactions.

Keywords: Amphetamine-induced efflux; Cell signaling and phosphorylation; Continuum mean-field theory; Electrostatic interactions; Lipid segregation in the membrane; Membrane composition and PIP(2) lipids; Molecular dynamics; Molecular dynamics simulations; Psychostimulant drugs of abuse.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Dopamine Plasma Membrane Transport Proteins / chemistry
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Humans
  • Membrane Lipids / chemistry*
  • Membrane Lipids / metabolism
  • Membrane Transport Proteins / chemistry*
  • Membrane Transport Proteins / metabolism
  • Models, Molecular
  • Neurotransmitter Transport Proteins / chemistry*
  • Neurotransmitter Transport Proteins / metabolism
  • Phosphatidylinositol 4,5-Diphosphate / chemistry
  • Phosphatidylinositol 4,5-Diphosphate / metabolism
  • Protein Binding
  • Protein Structure, Tertiary*
  • Serotonin Plasma Membrane Transport Proteins / chemistry
  • Serotonin Plasma Membrane Transport Proteins / metabolism


  • Dopamine Plasma Membrane Transport Proteins
  • Membrane Lipids
  • Membrane Transport Proteins
  • Neurotransmitter Transport Proteins
  • Phosphatidylinositol 4,5-Diphosphate
  • Serotonin Plasma Membrane Transport Proteins