Glutamate Receptors: Family matters
Genome sequence data from a range of animal species are raising questions about the origins of glutamate receptors.
- National Institute for Neurological Disorders and Stroke, United States
- Pennsylvania State University, United States
Receptors for the amino acid glutamate have a crucial role in the nervous system of nearly all animals. These proteins are split between two families: metabotropic glutamate receptors modulate the activity of neural networks, while ionotropic glutamate receptors mediate the transmission of signals between neurons. While we know a great deal about glutamate receptors, the gigabytes of data from recent genome sequencing projects provide a new opportunity to dissect how they have evolved.
These growing genomic data have also prompted new ideas about the evolution of animals. According to a new – and still controversial – version of the animal tree of life (Figure 1), comb jellies, or ctenophores, evolved first (Moroz et al., 2014; Ryan et al., 2013). Sponges (porifera) appeared next, followed by placozoans, jellyfishes (cnidarians) and, finally, bilaterians, vertebrates and invertebrates with bilateral body symmetry. If this revised tree is correct (Jékely et al., 2015; Ryan, 2014), neurons could have been lost twice during evolution because comb jellies have a nervous system but sponges and placozoans do not. Now, in eLife, Àlex Bayés of the Biomedical Research Institute Sant Pau in Barcelona and colleagues – including David Ramos-Vicente as first author – report new insights into the evolution of glutamate receptors by conducting a comprehensive study of these proteins across different animal groups (Ramos-Vicente et al., 2018).
Figure 1
Two models for the evolution of glutamate receptors.
(A) For many years, it was assumed that porifera (sponges) were the earliest animals, but some researchers now argue that instead, ctenophores (comb jellies) evolved first. Yet, the details of how important aspects of the nervous system evolved remain unclear. Ramos-Vicente et al. propose that the sub-families of ionotropic glutamate receptors (Epsilon: orange; Lambda: grey; AKDF: blue; NMDA: red) were present in the last common ancestor (LCA) of all animals, with certain sub-families being lost (indicated by a cross) one or more times during evolution. (B) An alternative scheme, which we favor, proposes that a precursor of Epsilon receptors was the only family present in the last common ancestor. Gene duplication would have led to the evolution of the AKDF sub-family in the ancestor of placozoans, cnidaria and bilaterians, with the Lambda sub-family appearing only in sponges. Finally, another gene duplication event would have given rise to NMDA receptors in cnidarians and bilaterians.
Image credit: Vignettes from phylopic.org. Ctenophores: Mali'o Kodis, photograph by Aqua-Photos; Porifera: Mali'o Kodis, photograph by Derek Keats (CC BY 3.0); Placozoans: Mali'o Kodis, photograph from Wikimedia (CC BY 3.0); Cnidaria: Qiang Ou (CC BY 3.0); Bilateria: Human (CC0), Hemichordata: Mali'o Kodis, drawing by Manvir Singh (CC BY 3.0).
Previously, researchers had identified four sub-families of ionotropic glutamate receptors, but they had mainly looked at vertebrate species. Now, Ramos-Vicente et al. muster data from other animal groups and propose a major reclassification that contains two new sub-families called Epsilon and Lambda. The NMDA receptors, which play a special role in vertebrates (Collingridge and Bliss, 1995), remain from the old classification, and the AKDF sub-family combines three other sub-families from the former model. Moreover, the team argues that all four sub-families were present in the last common ancestor of animals, with some being lost repeatedly during evolution (Figure 1A).
This would explain why the Epsilon sub-family is present in most animals today, whereas Lambda is only found in sponges. AKDF is carried by sponges, placozoans, jellyfish and bilaterians, but NMDA receptors exist only in these last two groups. However, we favor an alternative model in which the Epsilon sub-family evolved first, followed by the AKDF proteins. The Lambda receptors came next but only in sponges; then finally, the NMDA sub-family emerged in a common ancestor of jellyfish and bilaterians, persisting in these species (Figure 1B).
Amongst the newly identified sub-families, the Epsilon receptors are especially interesting because, like NMDA receptors, some of them are activated by glycine and others by glutamate. Such glycine receptors have previously been found in comb jellies (Alberstein et al., 2015; Yu et al., 2016), and now Ramos-Vicente et al. have identified them in a group of bilateral animals called lancelets, even though these organisms are separated from comb jellies by hundreds of millions of years of evolution. The receptors that get activated by glycine were more widespread than expected, with three receptors preferring glycine for every two favoring glutamate.
Deciphering the genetic sequence of a protein helps to predict its final structure. These analyses revealed that in comb jellies and lancelets, a subset of ionotropic glutamate receptors lacks the molecular features required to bind neurotransmitter amino acids, which suggests that they attach to other, as yet unidentified molecules. Surprisingly, when modeling the structure of one of the Epsilon receptors found in lancelets, it appeared that it might not be able to bind a ligand at all. This feature was seen in five Epsilon subunits and six AKDF subunits in these animals.
Many of the new receptors reported by Ramos-Vicente et al. have been identified only by analyzing their genetic sequences; their functional properties have yet to be studied either in native tissues, which is a challenge for many marine creatures, or by expressing these proteins in model organisms. When this is done, our understanding of the diversity of glutamate receptors will expand enormously.
References
-
Memories of NMDA receptors and LTPTrends in Neurosciences 18:54–56.https://doi.org/10.1016/0166-2236(95)80016-U
Article and author information
Author details
Publication history
- Version of Record published: December 28, 2018 (version 1)
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Metrics
-
- 1,409
- Page views
-
- 150
- Downloads
-
- 2
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Glutamate Receptors: Family matters
eLife 7:e43815.
https://doi.org/10.7554/eLife.43815
Further reading
-
- Evolutionary Biology
- Genetics and Genomics
The genetic variants introduced into the ancestors of modern humans from interbreeding with Neanderthals have been suggested to contribute an unexpected extent to complex human traits. However, testing this hypothesis has been challenging due to the idiosyncratic population genetic properties of introgressed variants. We developed rigorous methods to assess the contribution of introgressed Neanderthal variants to heritable trait variation relative to that of modern human variants. We applied these methods to analyze 235,592 introgressed Neanderthal variants and 96 distinct phenotypes measured in about 300,000 unrelated white British individuals in the UK Biobank. Introgressed Neanderthal variants have a significant contribution to trait variation consistent with the polygenic architecture of complex phenotypes (contributing 0.12% of heritable variation averaged across phenotypes). However, the contribution of introgressed variants tends to be significantly depleted relative to modern human variants matched for allele frequency and linkage disequilibrium (about 59% depletion on average), consistent with purifying selection on introgressed variants. Different from previous studies (McArthur 2021), we find no evidence for elevated heritability across the phenotypes examined. We identified 348 independent significant associations of introgressed Neanderthal variants with 64 phenotypes . Previous work (Skov 2020) has suggested that a majority of such associations are likely driven by statistical association with nearby modern human variants that are the true causal variants. We therefore developed a customized statistical fine-mapping methodology for introgressed variants that led us to identify 112 regions (at a false discovery proportion of 16%) across 47 phenotypes containing 4,303 unique genetic variants where introgressed variants are highly likely to have a phenotypic effect. Examination of these variants reveal their substantial impact on genes that are important for the immune system, development, and metabolism. Our results provide the first rigorous basis for understanding how Neanderthal introgression modulates complex trait variation in present-day humans.
-
- Ecology
- Evolutionary Biology
Spider venoms are a complex concoction of enzymes, polyamines, inorganic salts, and disulfide-rich peptides (DRPs). Although DRPs are widely distributed and abundant, their bevolutionary origin has remained elusive. This knowledge gap stems from the extensive molecular divergence of DRPs and a lack of sequence and structural data from diverse lineages. By evaluating DRPs under a comprehensive phylogenetic, structural and evolutionary framework, we have not only identified 78 novel spider toxin superfamilies but also provided the first evidence for their common origin. We trace the origin of these toxin superfamilies to a primordial knot – which we name ‘Adi Shakti’, after the creator of the Universe according to Hindu mythology – 375 MYA in the common ancestor of Araneomorphae and Mygalomorphae. As the lineages under evaluation constitute nearly 60% of extant spiders, our findings provide fascinating insights into the early evolution and diversification of the spider venom arsenal. Reliance on a single molecular toxin scaffold by nearly all spiders is in complete contrast to most other venomous animals that have recruited into their venoms diverse toxins with independent origins. By comparatively evaluating the molecular evolutionary histories of araneomorph and mygalomorph spider venom toxins, we highlight their contrasting evolutionary diversification rates. Our results also suggest that venom deployment (e.g. prey capture or self-defense) influences evolutionary diversification of DRP toxin superfamilies.
