Metazoan evolution and diversity of glutamate receptors and their auxiliary subunits

Neuropharmacology. 2021 Sep 1:195:108640. doi: 10.1016/j.neuropharm.2021.108640. Epub 2021 Jun 8.


Glutamate is the major excitatory neurotransmitter in vertebrate and invertebrate nervous systems. Proteins involved in glutamatergic neurotransmission, and chiefly glutamate receptors and their auxiliary subunits, play key roles in nervous system function. Thus, understanding their evolution and uncovering their diversity is essential to comprehend how nervous systems evolved, shaping cognitive function. Comprehensive phylogenetic analysis of these proteins across metazoans have revealed that their evolution is much more complex than what can be anticipated from vertebrate genomes. This is particularly true for ionotropic glutamate receptors (iGluRs), as their current classification into 6 classes (AMPA, Kainate, Delta, NMDA1, NMDA2 and NMDA3) would be largely incomplete. New work proposes a classification of iGluRs into 4 subfamilies that encompass 10 classes. Vertebrate AMPA, Kainate and Delta receptors would belong to one of these subfamilies, named AKDF, the NMDA subunits would constitute another subfamily and non-vertebrate iGluRs would be organised into the previously unreported Epsilon and Lambda subfamilies. Similarly, the animal evolution of metabotropic glutamate receptors has resulted in the formation of four classes of these receptors, instead of the three currently recognised. Here we review our current knowledge on the animal evolution of glutamate receptors and their auxiliary subunits. This article is part of the special issue on 'Glutamate Receptors - Orphan iGluRs'.

Keywords: AMPA receptor Auxiliary subunit; Glutamatergic synapse evolution; Ionotropic glutamate receptor; Metabotropic glutamate receptor; Phylogeny.

Publication types

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

MeSH terms

  • Animals
  • Evolution, Molecular
  • Glutamic Acid / metabolism
  • Phylogeny
  • Protein Subunits / metabolism*
  • Receptors, Glutamate / metabolism*


  • Protein Subunits
  • Receptors, Glutamate
  • Glutamic Acid