Evolutionary history of histamine receptors: Early vertebrate origin and expansion of the H3-H4 subtypes

Histamine receptors belonging to the superfamily of G protein-coupled receptors (GPCRs) mediate the diverse biological effects of biogenic histamine. They are classified into four phylogenetically distinct subtypes H-1-H-4, each with a different binding affinity for histamine and divergent downstream signaling pathways. Here we present the evolutionary history of the histamine receptors using a phylogenetic approach complemented with comparative genomics analyses of the sequences, gene structures, and synteny of gene neighborhoods. The data indicate the earliest emergence of histamine-mediated GPCR signaling by a H-2 in a prebilaterian ancestor. The analyses support a revised classification of the vertebrate H-3-H-4 receptor subtypes. We demonstrate the presence of the H-4 across vertebrates, contradicting the currently held notion that H-4 is restricted to mammals. These non mammalian vertebrate H-4 orthologs have been mistaken for H-3. We also identify the presence of a new H-3 subtype (H3B), distinct from the canonical H-3 (H(3)A), and propose that the H(3)A, H3B, and H-4 likely emerged from a H-3 progenitor through the 1R/2R whole genome duplications in an ancestor of the vertebrates. It is apparent that the ability of the H-1, H-2, and H3-4 to bind histamine was acquired convergently. We identified genomic signatures suggesting that the H-1 and H-3-H-4 shared a last common ancestor with the muscarinic receptor in a bilaterian predecessor whereas, the H-2 and the alpha-adrenoreceptor shared a progenitor in a prebilaterian ancestor. Furthermore, site-specific analysis of the vertebrate subtypes revealed potential residues that may account for the functional divergence between them.

Automated summary

This study uses phylogenetic and comparative genomics analyses to reveal the evolutionary history of histamine receptors, proposing a revised classification of the vertebrate H-3-H-4 receptor subtypes. It challenges the notion that H-4 is restricted to mammals and identifies a new H-3 subtype (H3B). The study also suggests that the ability of H-1, H-2, and H3-4 to bind histamine was acquired convergently.