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

Abstract

Biogenic amine receptors play critical roles in regulating behavior and physiology in both vertebrates and invertebrates, particularly within the central nervous system. Members of the G-protein coupled receptor (GPCR) family, these receptors interact with endogenous bioamine ligands such as dopamine, serotonin, and epinephrine, and are targeted by a wide array of pharmaceuticals. Despite the clear clinical and biological importance of these receptors, 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 sequence alignment of vertebrate biogenic amine receptors. In particular, we have integrated a traditional multiple sequence approach with robust structural domain predictions to ensure that alignment columns accurately capture the highly-conserved GPCR structural domains, and we demonstrate how ignoring structural information produces spurious inferences of homology. Using this alignment, we have constructed a structurally-partitioned maximum-likelihood phylogeny from which 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.

Identification of genes related to learning and memory in the brain transcriptome of the mollusc,Hermissenda crassicornis

“…1A). As previously shown, 5-HT2 receptors clustered with dopamine D2 receptors, whereas 5-HT6 genes were more closely related to dopamine D1 receptors (Mustard et al 2005;Nagakura et al 2010;Spielman et al 2015).We confirmed the existence of the 5-HT6 gene in the Aplysia (aplysiagenetools.org) and Tritonia brain transcriptomes. DNA plasmids were generated by three or more independent PCR reactions, followed by cloning to pGEM-T Easy vectors.…”

“…1A). As previously shown, 5-HT2 receptors clustered with dopamine D2 receptors, whereas 5-HT6 genes were more closely related to dopamine D1 receptors (Mustard et al 2005;Nagakura et al 2010;Spielman et al 2015).…”

Phylogenetic evidence suggests a later origin of the DRD2l and DRD4rs dopamine receptor gene lineages

“…There ie aleo a caee in which the membere of the DRD1 claee of dopamine receptore have been recovered ae two dietinct cladee, one that includee DRD1 and DRD5 and another grouping DRD1C and DRD1E (Yamamoto et al, 2015). In contraet to the lack of phylogenetic agreement among the DRD1 claee of dopamine receptore, phylogenetic relationehipe among the membere of the DRD2 claee of dopamine receptore are well reeolved ae in moet etudiee DRD2 ie recovered eieter to DRD3, whereae DRD4 ie recovered eieter to the DRD2/DRD3 clade (Callier et al, 2003;Haug-Baltzell et al, 2015;Spielman, Kumar & Wilke, 2015;Yamamoto et al, 2015). Underetanding the time of origin of the different dopamine receptore ie aleo an ieeue that neede further etudy, eepecially for the genee that poeeeee reetricted phyletic dietributione (e.g.…”

“…Baeed on their pharmacological propertiee, dopamine receptore are claeeified into two major groupe: the DRD1 group, which includee DRD1, DRD5, DRD1C, and DRD1E; and the DRD2 group that includee DRD2, DRD2l, DRD3 DRD4, and DRD4re (Yamamoto et al, 2015). Today it ie well known that theee groupe originated independently euch that the ability to bind dopamine wae acquired twice during the evolution of biogenic amine receptore (Callier et al, 2003;Yamamoto et al, 2013Yamamoto et al, , 2015Spielman, Kumar & Wilke, 2015). Although both groupe ehare the ability to bind dopamine, they aleo ehow the eignature of their independent hietoriee ae they differ in eeveral other characterietice (Sibley, 1999;Beaulieu & Gainetdinov, 2011).…”

Evolutionary considerations on 5-HT2 receptors

“…Within the Rhodopsin-like GPCR family, biogenic amine receptors likely emerged together with the Fungi and Metazoan lineage. In Metazoan, the diversification of biogenic amine GPCRs has largely contributed to the physiological expansion of peripheral and of central nervous system complexity [2].…”