Research published in Open Biology

Drs. David Ramos-Vicente and Alex Bayés, researchers of the Research Group Molecular Physiology of Synapses of the Sant Pau Research Institute-IIB Sant Pau have recently published the article “AMPA receptor auxiliary subunit auxiliary emerged during early vertebrate evolution by neo / subfunctionalization of unrelated proteins “in the scientific journal Open Biology published by the Royal Society.

Synapses are the specialized structures through which neurons communicate, using specific molecules, the neurotransmitters. The amino acid glutamate is the main excitatory neurotransmitter in the nervous system of animals. When a neuron, the presynaptic neuron, is activated, it transmits this signal by releasing glutamate into the synaptic space where it will act on the receptors present on the membrane of another neuron, called postsynaptic.

Ionotropic glutamate receptors (iGluRs) are ion channels that open when this amino acid binds, thus mediating rapid signal transmission. The iGluRs at synapses are accompanied by several auxiliary proteins (subunits), which modify and regulate their activity. Specifically, AMPA-type iGluRs have up to 14 different auxiliary subunits that combine in various ways to accompany and regulate these receptors, forming what we call the AMPA complex. These auxiliary subunits belong to several protein families, which are groups of proteins with a common evolutionary origin and structurally related. Although the AMPA complex is well known in mammals, we know little about its origin and evolution.

This study aims to establish the evolutionary history of protein families containing AMPA receptor auxiliary subunits (referred to as ARAS) in the animal kingdom. For this purpose, several bioinformatics tools have been used, mainly the construction of phylogenetic trees, which allow us to know the genealogy of the different protein families, and multiple sequence alignments, which allow us to compare the amino acids that make up the proteins. The results show how these families are evolutionarily ancient, being two of them, called Cornichon and Dispanin C, present in the common ancestor of all animals, and the other two, called CACNG-GSG1 and shiso, in the ancestor of animals with bilateral symmetry (which include among others many insects, Annelida, mollusks, echinoderms and vertebrates).

Phylogenetic trees have predicted that members of three of these families (Cornichon, CACNG-GSG1 and Dispanin C) could act as RAAs in invertebrate organisms. However, in vertebrates, the expansion of the number of proteins belonging to the CACNG-GSG1 family, as well as processes of subfunctionalization (functional specialization) of the member proteins of the Cornichon and Dispanin C families and neofunctionalization (acquisition of new functions) of proteins of the shiso family, would have increased and diversified the repertoire of RAAs present in these organisms. This would have increased the regulatory capacity of AMPA receptors as well as the variety of responses to glutamate release by the presynaptic neuron. This has led to hypothesize that the recruitment of several proteins at the synapse to act as RAAs would be an important evolutionary step in the increase of the complexity of the vertebrate nervous system. In the brain of these organisms, glutamatergic neurotransmission is involved in several cognitive tasks, such as learning and memory formation. Its alteration causes pathologies such as schizophrenia, intellectual disability and is related to Alzheimer’s disease. Thus, knowing the evolution of the proteins that are part of the glutamatergic synapse helps us to better understand this complex structure.

David Ramos-Vicente and Àlex Bayés. AMPA receptor auxiliary subunits emerged during early vertebrate evolution by neo/subfunctionalization of unrelated proteins. Open Biol. 2020 Oct;10(10):200234. doi: 10.1098/rsob.200234.

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