Comprehensive, structurally-curated alignment and phylogeny of vertebrate biogenic amine receptors

Abstract

Biogenic amine receptors play critical roles in regulating behavior and physiology, particularly within the central nervous system, in both vertebrates and invertebrates. These receptors belong to the G-protein coupled receptor (GPCR) family and interact with endogenous bioamine ligands, such as dopamine, serotonin, and epinephrine, and they are targeted by a wide array of pharmaceuticals. Despite these receptors’ clear clinical and biological importance, their evolutionary history remains poorly characterized. In particular, the relationships among biogenic amine receptors and any specific evolutionary constraints acting within distinct receptor subtypes are largely unknown. To advance and facilitate studies in this receptor family, we have constructed a comprehensive, high-quality, structurally-curated sequence alignment of vertebrate biogenic amine receptors. We demonstrate that aligning GPCR sequences without considering structure produces an alignment with substantial error, whereas a structurally-aware approach greatly improves alignment accuracy. Moreover, we show that phylogenetic inference with our structurally-curated alignment offers dramatic improvements over a structurally-naive alignment. Using the structural alignment and its corresponding phylogeny, we deduce novel biogenic amine receptor relationships and uncover previously unrecognized lineage-specific receptor clades. Moreover, we find that roughly 1% of the 3039 sequences in our final alignment are either misannotated or unclassified, and we propose updated classifications for these receptors. We release our comprehensive alignment and its corresponding phylogeny as a resource for future research into the evolution and diversification of biogenic amine receptors.

Evolution of the α2-adrenoreceptors in vertebrates: ADRA2D is absent in mammals and crocodiles

“…In agreement with previous results, the clade that includes dopamine receptors (DRD) 2, 3 and 4 was recovered as sister to the ADRA2 clade (Spielman et al, 2015;Zavala et al, 2017). Although we expected dopamine receptors (DRD) 1 and 5 to be sister to the βadrenoreceptors (ADRB) (Spielman et al, 2015;Zavala et al, 2017), this was not the case. This could mainly be due to the fact that the sampling effort performed in this study was not aimed at resolving the evolutionary relationship among these genes.…”