Abstract
The gut hormone ghrelin is involved in numerous metabolic functions, such as the stimulation of growth hormone secretion, gastric motility, and food intake. Ghrelin is modified by ghrelin O‐acyltransferase (GOAT) or membrane‐bound O‐acyltransferase domain‐containing 4 (MBOAT4) enabling action through the growth hormone secretagogue receptors (GHS‐R). During the course of evolution, initially strong ligand/receptor specificities can be disrupted by genomic changes, potentially modifying physiological roles of the ligand/receptor system. Here, we investigated the coevolution of ghrelin, GOAT, and GHS‐R in vertebrates. We combined similarity search, conserved synteny analyses, phylogenetic reconstructions, and protein structure comparisons to reconstruct the evolutionary history of the ghrelin system. Ghrelin remained a single‐gene locus in all vertebrate species, and accordingly, a single GHS‐R isoform was identified in all tetrapods. Similar patterns of the nonsynonymous (dN) and synonymous (dS) ratio (dN/dS) in the vertebrate lineage strongly suggest coevolution of the ghrelin and GHS‐R genes, supporting specific functional interactions and common physiological pathways. The selection profiles do not allow confirmation as to whether ghrelin binds specifically to GOAT, but the ghrelin dN/dS patterns are more similar to those of GOAT compared to MBOAT1 and MBOAT2 isoforms. Four GHS‐R isoforms were identified in teleost genomes. This diversification of GHS‐R resulted from successive rounds of duplications, some of which remained specific to the teleost lineage. Coevolution signals are lost in teleosts, presumably due to the diversification of GHS‐R but not the ghrelin gene. The identification of the GHS‐R diversity in teleosts provides a molecular basis for comparative studies on ghrelin's physiological roles and regulation, while the comparative sequence and structure analyses will assist translational medicine to determine structure–function relationships of the ghrelin/GHS‐R system.
Highlights
Complex physiological networks are integrated through ligand/binding-receptor physical interactions (Howard et al 1996; Kaiya et al 2014a) to regulate essential physiological functions such as growth, reproduction, behavior, homeostasis, and metabolism (Tscho€p et al 2000; Asakawa et al 2005; Chen et al 2009; Kojima and Kangawa 2010; Kitazawa et al 2012; Mu€ller et al 2015)
The ghrelin of teleost fishes including D. rerio and the cave fish, A. mexicanus, is flanked downstream by TatD DNAse domain-containing 2 (TATDN2) but upstream is flanked by a different gene annotated as coiled coil domain-containing 174 (CCDC174)
In addition to confirming the presence of a single ghrelin locus in vertebrates, one growth hormone secretagogue receptors (GHS-R) isoform in all tetrapods and three isoforms previously characterized in fishes, we identified two new GHS-R variants in teleosts
Summary
Complex physiological networks are integrated through ligand/binding-receptor physical interactions (Howard et al 1996; Kaiya et al 2014a) to regulate essential physiological functions such as growth, reproduction, behavior, homeostasis, and metabolism (Tscho€p et al 2000; Asakawa et al 2005; Chen et al 2009; Kojima and Kangawa 2010; Kitazawa et al 2012; Mu€ller et al 2015). The activation of heterotrimeric G protein mediates the actions of signaling proteins such as neuroendocrine peptides by allowing the translation of extracellular signals into the intracellular space (Kaiya et al 2008, 2014a). Receptors and their peptide ligands originated from common ancestral genes and may have diversified through gene duplication (Meyer and Schartl 1999; Meijer et al 2007) (Miki et al 1992; Chan and Cheng 2004), retrotransposition
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