The Remarkable Conservation of Corticotropin-Releasing Hormone (CRH)-Binding Protein in the Honeybee (Apis mellifera) Dates the CRH System to a Common Ancestor of Insects and Vertebrates

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Abstract
CRH-binding protein (CRH-BP) is a key factor in the regulation of CRH signaling; it modulates the bioactivity and bioavailability of CRH and its related peptides. The conservation of CRH-BP throughout vertebrates was only recently demonstrated. Here we report the presence of CRH-BP in the honeybee (Apis mellifera) and other insects. Honeybee CRH-BP resembles previously characterized vertebrate CRH-BP sequences with respect to conserved cysteine residues, gene organization, and overall sequence identity. Phylogenetic analyses confirm the unambiguous orthology of insect and vertebrate CRH-BP sequences. Soon after their discovery, it was noted that insect diuretic hormone-I (DH-I) and its receptor share similarities with the vertebrate CRH family and their receptors. Despite these similarities, demonstration of common ancestry of DH-I and the vertebrate CRH family is still speculative: the mature neuropeptides are short, and their genes differ substantially with regard to the number of coding exons. Moreover, DH and CRH receptors belong to the much larger family of G protein-coupled receptors. In contrast, the unique and conspicuous features of CRH-BP greatly facilitate the establishment of orthology over much larger evolutionary distances. The identification of CRH-BP in insects clearly indicates that this gene predates vertebrates by at least several hundred million years. Moreover, our findings imply that a CRH system is shared by insects and vertebrates alike and, consequently, that it has been present at least since the common ancestor to both phylogenetic lines of proto- and deuterostomians.