Early Evolution of Ionotropic GABA Receptors and Selective Regimes Acting on the Mammalian-Specific Theta and Epsilon Subunits

Abstract

BackgroundThe amino acid neurotransmitter GABA is abundant in the central nervous system (CNS) of both invertebrates and vertebrates. Receptors of this neurotransmitter play a key role in important processes such as learning and memory. Yet, little is known about the mode and tempo of evolution of the receptors of this neurotransmitter. Here, we investigate the phylogenetic relationships of GABA receptor subunits across the chordates and detail their mode of evolution among mammals.Principal FindingsOur analyses support two major monophyletic clades: one clade containing GABAA receptor α, γ, and ε subunits, and another one containing GABAA receptor ρ, β, δ, θ, and π subunits. The presence of GABA receptor subunits from each of the major clades in the Ciona intestinalis genome suggests that these ancestral duplication events occurred before the divergence of urochordates. However, while gene divergence proceeded at similar rates on most receptor subunits, we show that the mammalian-specific subunits θ and ε experienced an episode of positive selection and of relaxed constraints, respectively, after the duplication event. Sites putatively under positive selection are placed on a three-dimensional model obtained by homology-modeling.ConclusionsOur results suggest an early divergence of the GABA receptor subunits, before the split from urochordates. We show that functional changes occurred in the lineages leading to the mammalian-specific subunit θ, and we identify the amino acid sites putatively responsible for the functional divergence. We discuss potential consequences for the evolution of mammals and of their CNS.

Expression of the Eight GABAA Receptor α Subunits in the Developing Zebrafish Central Nervous System

“…The evolution of the GABA A receptor gene family has been examined by using sequence data from a wide variety of species, including humans, rodents, canary, chicken, frogs and pufferfish, tunicates, C. elegans and drosophila [41, 42]. Our results are in line with these studies in finding that mammalian θ and ε subunits are more distinct compared to other subunits, such that their existence outside of the mammalian lineage is unclear [43]. Even among mammalian species, for example comparing humans to rodents, these two subunits are very diverse, which suggests they are evolving at a much faster rate than other subunits [44].…”

GABAA receptors activate fish feeding behaviour via two distinct functional pathways

“…As a fundamental result, we proved the existence of two distinct molecular mechanisms regulating feeding behaviour through GABARs, which act in a partially competitive manner. Due to the relatively conservative nature of GABAR structure in vertebrates (Martyniuk et al, 2007), these two mechanisms with the given interaction should be expected in higher taxons as well as in fishes. If true, this makes C. gibelio a convenient and universal experimental model for further studies of GABAR effects on feeding behaviour.…”

Expression of GABAA receptor α3-, θ-, and ε-subunit mRNAs during rat CNS development and immunolocalization of the ε subunit in developing postnatal spinal cord

“…In addition, nucleotidic sequence analysis has shown a mammalian-specific evolution of ε and θ subunits (Martyniuk et al, 2007). Thus, a simultaneous study of ε , θ and α 3, based on their common chromosomal origin, was appropriate in order to indicate a temporary association and dissociation of their gene expressions during rat CNS development.…”