Molecular pharmacology of glutamate transporters, EAATs and VGLUTs

Brain Res Brain Res Rev. 2004 Jul;45(3):250-65. doi: 10.1016/j.brainresrev.2004.04.004.


L-Glutamate serves as a major excitatory neurotransmitter in the mammalian central nervous system (CNS) and is stored in synaptic vesicles by an uptake system that is dependent on the proton electrochemical gradient (VGLUTs). Following its exocytotic release, glutamate activates fast-acting, excitatory ionotropic receptors and slower-acting metabotropic receptors to mediate neurotransmission. Na+-dependent glutamate transporters (EAATs) located on the plasma membrane of neurons and glial cells rapidly terminate the action of glutamate and maintain its extracellular concentration below excitotoxic levels. Thus far, five Na+-dependent glutamate transporters (EAATs 1-5) and three vesicular glutamate transporters (VGLUTs 1-3) have been identified. Examination of EAATs and VGLUTs in brain preparations and by heterologous expression of the various cloned subtypes shows these two transporter families differ in many of their functional properties including substrate specificity and ion requirements. Alterations in the function and/or expression of these carriers have been implicated in a range of psychiatric and neurological disorders. EAATs have been implicated in cerebral stroke, epilepsy, Alzheimer's disease, HIV-associated dementia, Huntington's disease, amyotrophic lateral sclerosis (ALS) and malignant glioma, while VGLUTs have been implicated in schizophrenia. To examine the physiological role of glutamate transporters in more detail, several classes of transportable and non-transportable inhibitors have been developed, many of which are derivatives of the natural amino acids, aspartate and glutamate. This review summarizes the development of these indispensable pharmacological tools, which have been critical to our understanding of normal and abnormal synaptic transmission.

Publication types

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

MeSH terms

  • Amino Acid Transport Systems, Neutral / agonists
  • Amino Acid Transport Systems, Neutral / antagonists & inhibitors
  • Amino Acid Transport Systems, Neutral / metabolism*
  • Animals
  • Carrier Proteins / agonists
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / metabolism*
  • Excitatory Amino Acid Transporter 1 / agonists
  • Excitatory Amino Acid Transporter 1 / antagonists & inhibitors
  • Excitatory Amino Acid Transporter 1 / metabolism*
  • Glutamic Acid / analogs & derivatives
  • Glutamic Acid / metabolism
  • Glutamic Acid / pharmacology
  • Humans
  • Ligands
  • Membrane Transport Proteins*
  • Models, Neurological
  • Molecular Conformation
  • Molecular Structure
  • Neuroglia / drug effects
  • Neuroglia / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Structure-Activity Relationship
  • Vesicular Glutamate Transport Protein 1
  • Vesicular Transport Proteins*


  • Amino Acid Transport Systems, Neutral
  • Carrier Proteins
  • Excitatory Amino Acid Transporter 1
  • Ligands
  • Membrane Transport Proteins
  • SLC17A7 protein, human
  • Vesicular Glutamate Transport Protein 1
  • Vesicular Transport Proteins
  • Glutamic Acid