Regulation of Glutamate, GABA and Dopamine Transporter Uptake, Surface Mobility and Expression

Abstract

Neurotransmitter transporters limit spillover between synapses and maintain the extracellular neurotransmitter concentration at low yet physiologically meaningful levels. They also exert a key role in providing precursors for neurotransmitter biosynthesis. In many cases, neurons and astrocytes contain a large intracellular pool of transporters that can be redistributed and stabilized in the plasma membrane following activation of different signaling pathways. This means that the uptake capacity of the brain neuropil for different neurotransmitters can be dynamically regulated over the course of minutes, as an indirect consequence of changes in neuronal activity, blood flow, cell-to-cell interactions, etc. Here we discuss recent advances in the mechanisms that control the cell membrane trafficking and biophysical properties of transporters for the excitatory, inhibitory and modulatory neurotransmitters glutamate, GABA, and dopamine.

Keywords: GABA; dopamine; glutamate; surface mobility; transporter; uptake.

FIGURE 1

Crystal structure of Glt_Ph, a bacterial homolog of glutamate transporters (PDB: 2NWX). (A) Side view of the glutamate transporter trimer parallel to the membrane, using a ribbon (top) and a surface representation sliced through the center of the transporter basin (bottom). (B) As in A, viewed from the extracellular side of the membrane. Aspartate (magenta) and sodium ions (blue) are represented as spheres. (C) Summary of the main feature of the stoichiometric and non-stoichiometric current mediated by glutamate transporters in prokaryotes and eukaryotes, respectively. Image generated using The PyMOL Molecular Graphics System (Version 2.3.2; Schrödinger, 2010).

FIGURE 2

Crystal structure of LeuT_AA, a bacterial homolog of GABA transporters (PDB: 2A65). (A) Side view of the LeuT_Aa transporter parallel to the membrane, using a ribbon (top) and a surface representation sliced through the center of the transporter (bottom). (B) As in (A), viewed from the extracellular side of the membrane. Leu (magenta), sodium (blue), and chloride ions (green) are represented as spheres. (C) Summary of the main feature of the stoichiometric and non-stoichiometric current mediated by Leu and GABA transporters in prokaryotes and eukaryotes, respectively. Image generated using The PyMOL Molecular Graphics System (Version 2.3.2; Schrödinger, 2010).

FIGURE 3

Crystal structure of Drosophila melanogaster dDAT dopamine transporter (PDB: 4XP1). (A) Side view of the Drosophila dopamine transporter parallel to the membrane, using a ribbon (top) and a surface representation sliced through the center of the transporter (bottom). (B) As in A, viewed from the extracellular side of the membrane. L-Dopa (magenta), sodium (blue) and chloride ions (green) are represented as spheres. (C) Summary of the main feature of the stoichiometric and non-stoichiometric current mediated by LeuT (prokaryotic dopamine transporter homolog) and DAT transporters in eukaryotes, respectively. Image generated using The PyMOL Molecular Graphics System (Version 2.3.2; Schrödinger, 2010).