Abstract
Glutamate receptors are divided in two unrelated families: ionotropic (iGluR), driving synaptic transmission, and metabotropic (mGluR), which modulate synaptic strength. The present classification of GluRs is based on vertebrate proteins and has remained unchanged for over two decades. Here we report an exhaustive phylogenetic study of GluRs in metazoans. Importantly, we demonstrate that GluRs have followed different evolutionary histories in separated animal lineages. Our analysis reveals that the present organization of iGluRs into six classes does not capture the full complexity of their evolution. Instead, we propose an organization into four subfamilies and ten classes, four of which have never been previously described. Furthermore, we report a sister class to mGluR classes I-III, class IV. We show that many unreported proteins are expressed in the nervous system, and that new Epsilon receptors form functional ligand-gated ion channels. We propose an updated classification of glutamate receptors that includes our findings.
Highlights
Glutamate is the principal excitatory neurotransmitter in the central nervous system of animals (Fonnum, 1984; Danbolt, 2001; Pascual-Anaya and D’Aniello, 2006). It acts on two families of structurally unrelated receptors: ionotropic glutamate receptors, which are ligand-gated ion channels and G-protein coupled receptors (GPCRs), known as metabotropic glutamate receptors (Sobolevsky et al, 2009; Conn and Pin, 1997)
Assuming ctenophores as the sister group to all other animals (Moroz et al, 2014; Ryan et al, 2013), our data suggest that the three major duplication events leading to this four subfamilies occurred before the divergence of current animal phyla
We have performed what to our knowledge is the most comprehensive phylogenetic study of metazoan glutamate receptors. This has revealed that their evolutionary history is much more complex than what is currently acknowledged, especially for the family of ionotropic glutamate receptors (iGluRs)
Summary
Glutamate is the principal excitatory neurotransmitter in the central nervous system of animals (Fonnum, 1984; Danbolt, 2001; Pascual-Anaya and D’Aniello, 2006) It acts on two families of structurally unrelated receptors: ionotropic glutamate receptors (iGluRs), which are ligand-gated ion channels and G-protein coupled receptors (GPCRs), known as metabotropic glutamate receptors (mGluRs) (Sobolevsky et al, 2009; Conn and Pin, 1997). There are two families of glutamate receptors: ionotropic receptors, which can open or close ion channels in response to neurotransmitters and control the transmission of a signal, and metabotropic receptors, which are linked to a specific protein and control the strength of signal Our understanding of these two receptor families comes from animals with backbones, known as vertebrates. We present experimental evidence showing that unreported GluRs found in the basally divergent chordate Branchiostoma lanceolatum (amphioxus) are highly expressed in the nervous system and that members of the unreported Epsilon subfamily, the most phylogenetically spread among unreported groups, can form functional ligand-gated ion channels
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