Abstract
In mammalian synapses, the function of ionotropic glutamate receptors is critically modulated by auxiliary subunits. Most of these specifically regulate the synaptic localization and electrophysiological properties of AMPA-type glutamate receptors (AMPARs). Here, we comprehensively investigated the animal evolution of the protein families that contain AMPAR auxiliary subunits (ARASs). We observed that, on average, vertebrates have four times more ARASs than other animal species. We also demonstrated that ARASs belong to four unrelated protein families: CACNG-GSG1, cornichon, shisa and Dispanin C. Our study demonstrates that, despite the ancient origin of these four protein families, the majority of ARASs emerged during vertebrate evolution by independent but convergent processes of neo/subfunctionalization that resulted in the multiple ARASs found in present vertebrate genomes. Importantly, although AMPARs appeared and diversified in the ancestor of bilateral animals, the ARAS expansion did not occur until much later, in early vertebrate evolution. We propose that the surge in ARASs and consequent increase in AMPAR functionalities, contributed to the increased complexity of vertebrate brains and cognitive functions.
Highlights
Ionotropic glutamate receptors are key to the physiology of the nervous system, as they mediate fast excitatory neurotransmission [1]
Among protein families including AMPA receptor auxiliary subunits, CACNGs and GSG1s belong to the superfamily of claudins [32,69,70]
Phylogenetic analysis identified four subfamilies among CACNG-GSG1s: TARPs, GSG1s, voltagedependent calcium channels (VDCC) and a protostome-specific subfamily. As these are widely represented among bilaterian phyla, we propose that the ancestral CACNG-GSG1 experienced three duplication events before the split of bilaterians
Summary
Ionotropic glutamate receptors are key to the physiology of the nervous system, as they mediate fast excitatory neurotransmission [1]. Species with simple nervous systems, such as the sea anemone N. vectensis, have a similar number of ionotropic glutamate receptor subunits to animals with complex brains, such as mammals [2]. The subcellular traffic and function of ionotropic glutamate receptors is controlled by their auxiliary subunits [5]. These proteins add a new layer of complexity to glutamatergic transmission and might have contributed to an expanded functionality of these receptors in animals with complex brains. Sixteen proteins have been identified as ionotropic glutamate receptor auxiliary subunits. Fourteen modulate AMPAtype glutamate receptors (AMPARs) [6], and they are referred to as AMPA receptor auxiliary subunits (ARASs). Known mammalian ARASs belong to five protein families: CACNG and GSG1 (both within the superfamily of claudins), cornichon, shisa and Dispanin C
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